Exam 3 Flashcards
receptor
A receptor is a protein molecule located on the surface of or within a cell that binds to specific signaling molecules, called ligands, and initiates a cellular response.
signaling molecule
A signaling molecule is a molecule that carries information from one cell to another, usually through binding to a specific receptor on the surface of the target cell.
signal reception
Signal reception refers to the process by which a cell detects and responds to extracellular signals or stimuli through the binding of signaling molecules to specific receptors on the cell surface or within the cell.
signal transduction
Signal transduction is the process by which extracellular signals or stimuli are transmitted into the cell, leading to a cellular response. It typically involves a series of biochemical reactions that relay the signal from the cell surface or receptor to the cell interior, often involving the activation of intracellular signaling pathways and the modulation of gene expression, protein activity, or cellular processes.
signal response (final response)
Signal response, or final response, refers to the ultimate cellular or physiological changes elicited by a signaling pathway in response to extracellular signals or stimuli.
signal deactivation
Signal deactivation refers to the process by which cellular signaling pathways are terminated or attenuated after the initial signaling stimulus has been received and the cellular response has been elicited.
kinase cascade
A kinase cascade is a series of sequential phosphorylation events in which one kinase phosphorylates and activates another kinase, leading to amplification and propagation of a signaling pathway.
dimer (dimerize)
A dimer is a complex formed by the association of two identical or similar molecules, called monomers. Dimerization refers to the process by which these monomers come together to form a dimer.
Describe the components and the general process of signaling – reception, transduction, final
response, deactivation.
Reception:
- Signal molecules (ligands) bind to receptor proteins
- Receptors can be on cell surface or inside the cell
- Binding causes conformational change in receptor
Transduction:
- Conformational change in receptor triggers signal transduction pathway
- Involves sequential activation/modification of relay molecules
- Relay molecules include kinases, phosphatases, GTPases, etc.
- Amplifies and propagates signal within the cell
Response:
- Activated relay molecules regulate activity of effector molecules
- Effectors include transcription factors, enzymes, ion channels
- Transcription factors modulate gene expression
- Enzymes catalyze biochemical reactions
- Ion channels control ion flow and membrane potential
- Integrated responses lead to cellular changes (metabolism, movement, division, etc.)
General Process:
- Extracellular signal → receptor binding → transduction pathway → effector activation → cellular response
Be able to recognize the general steps of signaling in a diagram or word problem
Reception:
- Ligand (signal molecule) binding to receptor protein
- Receptor shown on cell surface or inside cell
Transduction:
- Activation/modification of relay molecules (kinases, phosphatases, GTPases, etc.)
- Sequential steps showing propagation of signal
- Arrows indicating direction of signal flow
Response:
- Activation of effector molecules (transcription factors, enzymes, ion channels)
- Cellular processes/changes resulting from effector activation (gene expression, metabolism, movement, etc.)
General Flow:
- Diagram/description should show progression from:
1. Extracellular signal (ligand)
2. Receptor binding
3. Relay molecule activation (transduction pathway)
4. Effector molecule activation
5. Cellular response/change
The key is identifying the reception, transduction, and response components and tracing the directional flow from signal to cellular outcome.
Be able to interpret the consequence of a change/mutation in a signaling pathway.
- Identify the specific component affected (receptor, relay molecule, effector)
- Determine if the change leads to:
- Gain of function (increased/constitutive activity)
- Loss of function (decreased/blocked activity)
Potential consequences:
- Receptor mutation:
- Gain of function = constant signal, even without ligand
- Loss of function = inability to receive signal
- Relay molecule mutation:
- Gain of function = amplified/unregulated signal propagation
- Loss of function = blocked signal transmission
- Effector mutation:
- Gain of function = effector constantly active
- Loss of function = inability to activate effector
- Consider downstream effects on cellular processes regulated by that pathway
- Cell cycle, metabolism, differentiation, apoptosis, etc.
- Interpret in the context of the specific cell type/tissue
- Effects may differ based on the pathway’s role
The key is tracing the functional impact of the mutation through the pathway, and deducing the potential cellular consequences based on the pathway’s normal role.
totipotent
Totipotent refers to the ability of a single cell to give rise to all cell types in an organism, including both embryonic and extraembryonic tissues, as well as supporting structures such as the placenta.
pluripotent
Pluripotent refers to the ability of a cell to differentiate into cells derived from all three germ layers of the embryo: ectoderm, endoderm, and mesoderm.
multipotent
Multipotent refers to the ability of a cell to differentiate into a limited number of cell types within a specific lineage or tissue type. Unlike pluripotent cells, which can differentiate into cells from all three germ layers, multipotent cells are more restricted in their differentiation potential and can give rise to a limited range of cell types within a particular lineage or tissue.
asymmetric cell division
Asymmetric cell division is a process in which a parent cell divides unequally to produce two daughter cells with distinct fates or properties. One daughter cell typically retains the characteristics of the parent cell, while the other daughter cell undergoes differentiation to acquire a specialized function or fate. This process is crucial for generating cell diversity during development and tissue homeostasis.
self-renewal
Self-renewal refers to the ability of a cell to undergo division and produce daughter cells that are identical to the parent cell, thus maintaining the cell’s population and characteristics over time. It is a fundamental property of stem cells, allowing them to proliferate and replenish themselves while also giving rise to differentiated cell types.
apoptosis (programmed cell death)
Apoptosis, also known as programmed cell death, is a tightly regulated process of cellular suicide that occurs in multicellular organisms. It plays essential roles in development, tissue homeostasis, and the elimination of damaged or unwanted cells. Apoptosis is characterized by distinct morphological changes, including cell shrinkage, chromatin condensation, DNA fragmentation, and the formation of apoptotic bodies, which are then engulfed and digested by neighboring cells or phagocytes.
primary vs. secondary sex characteristic
Primary Sex Characteristics:
- Develop during embryogenesis
- Direct reproductive organs and gamete production
- Examples:
- In males: testes, penis, seminal vesicles, prostate gland
- In females: ovaries, uterus, vagina, oviducts
Secondary Sex Characteristics:
- Develop during puberty
- Not directly involved in reproduction
- Influence by sex hormones (testosterone, estrogen)
- Examples in males:
- Deepening voice, facial/body hair growth, muscle mass increase
- Examples in females:
- Breast development, widening of hips, fat distribution pattern
Key Differences:
- Primary characteristics are essential for reproductive functions
- Secondary characteristics are non-reproductive traits influenced by hormones
- Primary characteristics develop before birth
- Secondary characteristics emerge during puberty
Both are important for overall sexual development and maturation, but primary characteristics directly facilitate the reproductive process.
primordial germ cell (PGC)
A primordial germ cell (PGC) is a precursor cell that gives rise to gametes (sperm and egg cells) during embryonic development. PGCs are specified early in embryogenesis and migrate to the developing gonads, where they undergo further differentiation and eventually differentiate into mature sperm or eggs. They are essential for the transmission of genetic information from one generation to the next.
differentiation
Differentiation is the process by which cells become specialized in structure and function to perform specific roles within an organism. It involves changes in gene expression and cellular morphology that lead to the acquisition of distinct characteristics and functions. Differentiation allows cells to adopt specific fates and perform specialized functions, contributing to the development and maintenance of tissues and organs in multicellular organisms.
biological sex
Biological sex refers to the classification of individuals as male or female based on their reproductive anatomy and physiology. It is determined primarily by genetic factors, such as the presence of sex chromosomes (XX for females, XY for males), which influence the development of reproductive structures and secondary sexual characteristics. Biological sex also encompasses hormonal and physiological differences between males and females, including differences in reproductive function and hormone levels.
Differences in Sex Development (DSD)
Definition:
- Congenital conditions where development of chromosomal, gonadal, or anatomical sex is atypical
Types:
- Sex Chromosome DSD
- Atypical number of X/Y chromosomes (e.g. XXY, XYY, XO)
- 46,XY DSD
- Typical male chromosomes, but atypical genital development
- 46,XX DSD
- Typical female chromosomes, but virilization of genitalia
Causes:
- Genetic mutations affecting hormone production/receptors
- Enzyme deficiencies disrupting hormone synthesis
- Environmental influences affecting hormone exposure
Consequences:
- Ambiguous genitalia at birth
- Discordance between internal/external genital development
- Potential issues with fertility, gender identity, hormone imbalances
Management:
- Multidisciplinary team (genetics, endocrine, psychology, surgery)
- Treatment tailored to specifics of condition
- Hormone therapy, surgery, psychosocial support as needed
Key Points:
- Spectrum of conditions with atypical biological sex characteristics
- Caused by genetic, hormonal, or environmental factors
- Can impact genital development, fertility, gender identity
- Requires specialized multidisciplinary care
Mullerian duct
The Müllerian duct, also known as the paramesonephric duct, is a paired embryonic structure present in both male and female embryos. In females, the Müllerian duct develops into the fallopian tubes, uterus, cervix, and upper two-thirds of the vagina, contributing to the female reproductive tract. In males, anti-Müllerian hormone secreted by the testes causes regression of the Müllerian ducts, while the Wolffian ducts develop into the male reproductive tract.
Wolffian duct
The Wolffian duct, also known as the mesonephric duct, is a paired embryonic structure present in both male and female embryos. In males, the Wolffian duct gives rise to the epididymis, vas deferens, and seminal vesicles, contributing to the male reproductive tract. In females, the Wolffian duct regresses under the influence of anti-Müllerian hormone secreted by the ovaries, while the Müllerian duct develops into the female reproductive tract.
Barr body
A Barr body is an inactivated X chromosome in the cells of female mammals. It appears as a condensed, darkly staining structure within the nucleus of cells, representing one of the two X chromosomes in females that undergo random X chromosome inactivation during embryonic development. This process ensures dosage compensation between males (XY) and females (XX) by equalizing the expression of X-linked genes between the sexes.
SRY, WNT4, FOXL2
SRY (Sex-determining Region Y):
- Located on Y chromosome
- Master regulator gene for male sex determination
- Initiates male developmental pathway in bipotential gonad
- Triggers differentiation of Sertoli cells and testosterone production
WNT4 (Wingless-type MMTV integration site family, member 4):
- Key ovarian development gene
- Expressed in female bipotential gonad
- Promotes differentiation into ovarian structures
- Antagonizes male pathway, allows granulosa cell development
FOXL2 (Forkhead box L2):
- Transcription factor crucial for ovarian development/maintenance
- Mutations cause premature ovarian failure
- Regulates aromatase expression for estrogen production
- Represses testicular pathway genes in ovary
Key Points:
- SRY initiates male pathway, WNT4/FOXL2 promote female pathway
- Antagonistic roles in sex determination from bipotential gonad
- Disruptions can lead to disorders of sex development (DSD)
- Tightly regulated spatio-temporal expression required for proper development
Be able to describe and recognize the 5 shared developmental processes – cell division
(asymmetric and symmetric), signaling, differentiation, cell movement, and apoptosis.
Cell Division:
- Asymmetric: Daughter cells have different developmental fates
- Symmetric: Daughter cells are identical
Signaling:
- Cell-cell communication via signaling molecules/pathways
- Drives pattern formation, cell fate specification
Differentiation:
- Cells become specialized cell types
- Gene expression changes alter cell structure/function
Cell Movement:
- Cells migrate to specific locations
- Important for gastrulation, organogenesis
Apoptosis:
- Programmed cell death
- Removes unnecessary/defective cells
Recognizing in diagrams/problems:
- Asymmetric division: Distinct daughter cell fates
- Signaling: Ligands, receptors, signal transduction components
- Differentiation: Cells changing shape, markers of specialized types
- Movement: Cells relocating from one region to another
- Apoptosis: Controlled cell death/removal of cells
The key is identifying which of these fundamental processes is occurring based on the cellular behaviors and outcomes described.
Be able to describe biological sex development in XY and XX individuals, connecting where
the 5 shared developmental processes (#1) appear throughout the process.
XY Individuals:
- Embryonic gonadal ridge is bipotential (undifferentiated)
- SRY gene (Y chromosome) initiates male pathway
- Signaling for Sertoli cell differentiation
- Sertoli cells produce AMH, inhibiting female pathways
- Signaling, apoptosis of female precursor cells
- Leydig cells differentiate, produce testosterone
- Signaling for male duct differentiation
- Cell movement: Mesonephric ducts form male internal genitalia
- Cell movement: Genital tubercle elongates to form penis/urethra
XX Individuals:
- Embryonic gonadal ridge is bipotential
- No SRY, allows ovarian developmental pathway
- Signaling promotes follicle cell differentiation
- Follicle cells produce estrogen, inhibit male pathways
- Signaling, apoptosis of male precursor cells
- Asymmetric cell divisions in oogonia produce egg cells
- Cell movement: Paramesonephric ducts form female internals
- Cell movement, signaling in genital tubercle for labia formation
In both cases, signaling initiates sex-specific differentiation cascades, with subsequent cell division, movement and apoptosis events orchestrating the development of mature reproductive anatomy.
Describe and recognize hormone receptor signaling in sex hormone signaling during development AND recognize the basic processes of cell signaling
Hormone Receptor Signaling in Sex Development:
- Sex hormones (testosterone, estrogen, etc.) act as ligands
- Bind to nuclear or membrane-bound receptors
- Nuclear receptors: Direct transcriptional regulation
- Membrane receptors: Activate signaling cascades
Receptor Types:
- Nuclear (e.g. androgen receptor, estrogen receptor)
- Ligand-receptor complex acts as transcription factor
- Membrane (e.g. GPCR, RTK)
- Ligand binding triggers signaling cascade
Basic Cell Signaling Processes:
1. Reception: Hormone binds to receptor protein
2. Transduction:
- Relay molecules relay/amplify signal (kinases, etc.)
- Forms signaling cascade
3. Response:
- Activate effector proteins (transcription factors, enzymes)
- Modulate gene expression, cellular processes
Recognizing in Diagrams/Problems:
- Hormone as ligand binding receptor
- Nuclear receptor –> direct gene regulation
- Membrane receptor –> signaling cascade components
- Sequential activation of relay molecules
- Transcriptional changes or altered cellular processes
The key is identifying the hormone/receptor interaction that initiates the signaling, and tracing the flow through the transduction cascade to the ultimate cellular response.
Understand sex identity must be maintained through mutual inhibition of the other sex determination pathway.
Key Concepts:
- Bipotential gonad can develop into testis or ovary initially
- Mechanisms ensure one pathway is firmly established and upheld
- The pathways antagonize and repress each other
Mutual Inhibition in Males (XY):
- SRY initiates testis pathway
- Sertoli cells produce Anti-Müllerian Hormone (AMH)
- AMH induces apoptosis/regression of Müllerian ducts (female pathway)
- Prevents development of female reproductive structures
Mutual Inhibition in Females (XX):
- No SRY allows ovarian pathway progression
- Ovarian somatic cells produce Estrogen
- Estrogen antagonizes/suppresses testis pathway genes
- WNT4/RSPO1 block male pathway, maintain ovarian identity
Importance:
- Ensures complete differentiation into one gonadal fate
- Avoids ambiguous intersex characteristics
- Maintains appropriate hormone milieu for sex development
The key is the pathways repress antagonistic factors from the opposite pathway through opposing signals and apoptosis of precursor cell types. This reinforces the established identity.
Understand that sex is not determined by sex chromosomes in all species
Key Concepts:
- In mammals, X and Y chromosomes initiate male (XY) or female (XX) pathway
- However, many other sex determination systems exist across species
Examples of Non-Chromosomal Sex Determination:
Environmental Sex Determination:
- Temperature-dependent sex determination in many reptiles/fish
- High vs low temperatures during development dictate sex
Haplodiploidy:
- Found in insects like honeybees
- Males arise from unfertilized haploid eggs, females from fertilized diploid eggs
Complementary Sex Determiners:
- Certain genes/loci must be matched for an individual to be male or female
- Example: X:A ratio in some crustaceans and insects
Genomic Imprinting/Parent-of-Origin Effects:
- Parental origin of sex chromosomes determines sex in some fish and amphibians
Impact:
- Demonstrates the diversity of sex determination mechanisms evolved
- Chromosomes are just one of many possible sex-determining factors
- Underscores that no single universal mechanism exists across life
The key is recognizing that while sex chromosomes regulate sex in mammals, numerous other genetic, environmental, and epigenetic cues control this process in other organisms.
Be able to explain if a particular part of hormone signaling is disrupted what might occur – like the AR mutation
AR Mutation Effects:
- AR is the nuclear receptor that binds testosterone/DHT
- Required for male virilization and sex differentiation
Potential Consequences of AR Mutation:
- Androgen Insensitivity Syndrome (AIS)
- Partial or complete inability to respond to androgens
Partial AIS:
- Undervirilization in males
- Ambiguous genitalia, micropenis, hypospadias
- Gyneccomastia (breast development) at puberty
Complete AIS:
- XY genotype, but complete female phenotype
- Undescended testes
- Absence of male reproductive structures
- Tall stature, lack of pubic/axillary hair
Other Impacts:
- Impaired masculinization of brain (male gender identity issues)
- Reduced bone/muscle mass
- Potential subfertility/infertility
Key Points:
- Disruption of AR blocks ability to respond to androgens
- Prevents proper male sexual differentiation and development
- Severity depends on degree of receptor dysfunction
The effects stem from the critical role of AR signaling in facilitating androgen-directed male characteristics during development and puberty. Impairment leads to undervirilization or complete feminization.
Understand that DSDs demonstrate how complex sex development is and the consequence of disruption in regulation or response of the developmental process
Complexity of Sex Development:
- Tightly regulated processes and pathways govern sex determination and differentiation
- Involves interplay of genes, hormones, receptors, and signaling cascades
- Small perturbations can have significant downstream effects
DSDs Highlight This Complexity:
- DSDs arise from disruptions at multiple points in the developmental program
- Causes include genetic mutations, enzyme defects, hormone imbalances, etc.
- Result in atypical reproductive anatomy, hormone levels, puberty, fertility
Specific Examples:
- Androgen insensitivity syndrome (dysfunctional androgen receptor)
- Congenital adrenal hyperplasia (enzyme deficiency disrupts hormone levels)
- Ovotesticular DSD (ambiguous gonadal differentiation)
- Sex chromosome aneuploidies (atypical X/Y combinations)
Consequences:
- Undervirilization or feminization in males
- Virilization or masculinization in females
- Ambiguous genitalia, impaired fertility, developmental delays
- Psychosocial issues related to gender identity/body image
Key Takeaway:
- DSD conditions underscore how tightly regulated sex development is
- Demonstrate widespread effects when any part of the process is perturbed
- Highlight the complex biology governing biological sex determination
You do not need to memorize different DSD mutations. I would give you a developmental
pathway and ask you if something is mutated what would happen
Reception/Signal Initiation:
- SRY mutation → Failure to initiate male pathway
- WNT4/RSPO1 mutation → Failure to initiate female pathway
- Hormone deficiency → Lack of signal to drive differentiation
Transduction/Signaling Cascades:
- Effector mutation (β-catenin, SOX9, etc.) → Blockade of that pathway
- Kinase/relay mutation → Impaired signal propagation/amplification
Transcriptional Regulation:
- Nuclear receptor mutation (AR, ER) → Inability to respond to hormones
- Transcription factor mutation → Failure of cell fate/differentiation programs
Hormone Synthesis/Levels:
- Enzyme mutation (ex. CYP17) → Disrupted hormone production
- Over/underproduction → Abnormal hormone exposure
Cellular Processes:
- Cell migration defect → Abnormal anatomy/structure positioning
- Proliferation/Survival defect → Incorrect cell numbers/populations
- Apoptosis dysregulation → Persistence of precursor cell types
Key Considerations:
- Identify component’s normal role and position in pathways
- Determine if mutation causes loss or gain of function
- Trace potential downstream impacts on differentiation, organogenesis
- Consider timing of disruption (stages affected)
The key is logically deducing how altering that component’s activity could derail downstream processes required for proper sex phenotype development.
electrochemical gradient
An electrochemical gradient refers to the combined influence of both an electrical gradient and a concentration gradient across a cell membrane or within an organelle. It represents the difference in electrical charge (voltage) and concentration of ions (such as sodium, potassium, calcium, or chloride) between two sides of a membrane. The electrochemical gradient drives the movement of ions across the membrane, influencing various cellular processes such as ion transport, membrane potential, and the generation of action potentials.
chemical gradient
A chemical gradient, also known as a concentration gradient, refers to the gradual change in the concentration of a substance (e.g., ions, molecules) over a distance. It exists when there is a difference in the concentration of a substance between two regions, such as inside and outside of a cell or across a membrane. Substances tend to move down their concentration gradient from areas of higher concentration to areas of lower concentration, a process known as passive diffusion. The magnitude of the chemical gradient influences the rate and direction of diffusion and other transport processes across biological membranes.
electrical gradient
An electrical gradient refers to the difference in electrical charge (voltage) between two regions, such as across a cell membrane or within an organelle. It arises from the separation of charges across the membrane, with one side being more positively charged and the other side more negatively charged. The electrical gradient influences the movement of charged particles, such as ions, across the membrane, affecting membrane potential and electrical signaling in cells. Ions tend to move toward regions of opposite charge along the electrical gradient, a process known as electrostatic attraction or repulsion.
passive transport
Passive transport is a process by which substances move across a cell membrane or biological membrane without the input of energy from the cell. It occurs along the concentration gradient or electrical gradient and does not require the use of ATP. Passive transport mechanisms include diffusion, facilitated diffusion, and osmosis, which allow substances such as ions, gases, and small molecules to move freely across the membrane to achieve equilibrium.
facilitated diffusion
Facilitated diffusion is a type of passive transport in which substances move across a cell membrane with the help of transport proteins. Unlike simple diffusion, facilitated diffusion involves the movement of substances down their concentration gradient but requires specific membrane proteins, such as channels or carriers, to facilitate their passage across the membrane. Facilitated diffusion does not require energy input from the cell and is used for the transport of large, polar, or charged molecules that cannot freely diffuse across the membrane.
primary active transport
Primary active transport is a process in which molecules or ions are transported across a cell membrane against their concentration gradient, using energy derived directly from the hydrolysis of ATP. This energy is used to change the conformation of specific transport proteins, such as pumps or ATPases, allowing them to actively transport molecules or ions across the membrane, typically from a region of lower concentration to a region of higher concentration. Primary active transport is essential for maintaining concentration gradients of ions (e.g., sodium, potassium, calcium) across cell membranes and is involved in various physiological processes, such as ion homeostasis, nerve impulse transmission, and muscle contraction.
membrane potential
Membrane potential refers to the difference in electrical charge (voltage) across a cell membrane or biological membrane. It is typically measured in millivolts (mV) and represents the separation of positive and negative charges across the membrane. Membrane potential arises from the uneven distribution of ions (such as sodium, potassium, chloride) across the membrane, with more positive ions on one side and more negative ions on the other. Membrane potential plays a critical role in various cellular processes, including the generation of action potentials in excitable cells, the regulation of ion transport, and the control of cell volume and pH.
polarization
Polarization refers to the establishment of a difference in electrical charge or potential between two points, regions, or across a membrane. In the context of cell biology, polarization often refers to the creation of a membrane potential across a cell membrane, resulting from the uneven distribution of ions. This polarization can play important roles in cellular processes such as signal transduction, cell communication, and the generation of electrical impulses in excitable cells.
depolarization
Depolarization refers to a change in the membrane potential of a cell, where the inside of the cell becomes less negative relative to the outside. This change occurs when positive ions, such as sodium ions (Na+), enter the cell, or negative ions, such as chloride ions (Cl-), exit the cell, disrupting the normal balance of charges across the membrane. Depolarization is often a key event in cellular signaling, such as the generation of action potentials in nerve cells or muscle cells, and can lead to various physiological responses.
hyperpolarization
Hyperpolarization refers to a change in the membrane potential of a cell, where the inside of the cell becomes more negative relative to the outside. This change occurs when positive ions, such as potassium ions (K+), exit the cell, or negative ions, such as chloride ions (Cl-), enter the cell, further increasing the normal negative charge inside the cell. Hyperpolarization makes the cell less excitable and less likely to generate an action potential. It often occurs in response to certain stimuli or as a result of the activity of ion channels.
dendrite
A dendrite is a branched extension of a neuron that receives signals from other neurons or sensory receptors. Dendrites are specialized to detect and transmit incoming electrical signals, called synaptic inputs, to the cell body (soma) of the neuron. They contain numerous dendritic spines, small protrusions where most excitatory synaptic connections occur. Dendrites play a critical role in integrating synaptic inputs and determining whether the neuron will generate an action potential.
cell body
The cell body, also known as the soma or perikaryon, is the main part of a neuron that contains the nucleus and most of the cell’s organelles, including the endoplasmic reticulum, Golgi apparatus, and mitochondria. It serves as the metabolic center of the neuron, responsible for maintaining cellular functions, protein synthesis, and energy production. The cell body integrates incoming signals from dendrites and generates outgoing signals, known as action potentials, which are transmitted along the neuron’s axon to communicate with other neurons or effector cells.
axon
The axon is a long, slender projection of a neuron that conducts electrical impulses away from the cell body to other neurons, muscles, or glands. It is specialized for transmitting signals over long distances, often extending from the cell body at one end and terminating in branching structures called axon terminals at the other end. Axons are covered by a myelin sheath, which acts as an insulating layer to increase the speed of signal transmission. Some axons can be quite long, allowing for rapid communication between distant regions of the nervous system.
axon terminal
The axon terminal, also known as the synaptic terminal or presynaptic terminal, is the specialized ending of an axon that forms synapses with target cells, such as other neurons, muscles, or glands. Axon terminals contain synaptic vesicles filled with neurotransmitter molecules, which are released into the synaptic cleft in response to an action potential arriving at the terminal. The neurotransmitters then diffuse across the synaptic cleft and bind to receptors on the membrane of the target cell, transmitting the signal from one neuron to the next or to the effector cell.
synapse
A synapse is a specialized junction between two neurons or between a neuron and its target cell, such as a muscle cell or gland. At the synapse, the axon terminal of the presynaptic neuron releases neurotransmitter molecules into the synaptic cleft, a small gap between the presynaptic terminal and the postsynaptic membrane of the target cell. The neurotransmitters diffuse across the synaptic cleft and bind to receptors on the postsynaptic membrane, leading to changes in the electrical potential of the postsynaptic cell and transmitting the signal from one neuron to the next. Synapses play a crucial role in communication within the nervous system, allowing for the transmission of information between neurons and the integration of neural activity.
presynaptic
Presynaptic refers to the region of a synapse that is located before the synaptic cleft, typically referring to the axon terminal of the presynaptic neuron. In the presynaptic region, neurotransmitter molecules are stored in synaptic vesicles and released into the synaptic cleft in response to an action potential arriving at the axon terminal. The release of neurotransmitters from the presynaptic neuron triggers changes in the postsynaptic neuron or target cell, leading to signal transmission across the synapse.
post synaptic
Postsynaptic refers to the region of a synapse that is located after the synaptic cleft, typically referring to the membrane of the target cell or postsynaptic neuron. In the postsynaptic region, neurotransmitter receptors are located on the membrane, where they bind to neurotransmitter molecules released from the presynaptic neuron. Activation of postsynaptic receptors leads to changes in the electrical potential of the postsynaptic cell, either depolarizing or hyperpolarizing it and transmitting the signal from one neuron to the next or to the effector cell.
action potential
An action potential is a brief, transient change in the electrical potential across the membrane of a nerve cell or muscle cell, characterized by a rapid depolarization followed by repolarization. It is initiated by a stimulus that causes a temporary reversal of the membrane potential, allowing positively charged ions, such as sodium (Na+) and potassium (K+), to flow into or out of the cell. This rapid change in membrane potential propagates along the length of the cell membrane, transmitting electrical signals over long distances within the nervous system. Action potentials are the basis for nerve impulse transmission and are essential for communication between neurons and for muscle contraction.
ligand-gated ion channel
A ligand-gated ion channel is a type of ion channel protein that opens or closes in response to the binding of a specific ligand molecule, such as a neurotransmitter or hormone. When the ligand binds to the receptor site on the ion channel, it causes a conformational change in the protein, allowing ions, such as sodium (Na+), potassium (K+), calcium (Ca2+), or chloride (Cl-), to flow across the cell membrane through the channel pore. Ligand-gated ion channels play crucial roles in synaptic transmission, sensory perception, and cellular signaling by regulating the flow of ions into or out of cells in response to extracellular signals.
voltage-gated ion channel
A voltage-gated ion channel is a type of ion channel protein that opens or closes in response to changes in membrane potential or voltage across the cell membrane. When the membrane potential reaches a certain threshold, the channel undergoes a conformational change, allowing ions, such as sodium (Na+), potassium (K+), calcium (Ca2+), or chloride (Cl-), to flow across the membrane through the channel pore. Voltage-gated ion channels play crucial roles in generating and propagating action potentials in excitable cells, such as neurons and muscle cells, by regulating the flow of ions in response to changes in membrane potential.
repolarization
Repolarization is the process in which a cell’s membrane potential returns to its resting state after depolarization, typically following an action potential or other excitatory event. During repolarization, the membrane potential becomes more negative, restoring the electrical charge across the cell membrane. This is usually achieved by the efflux of positively charged ions, such as potassium (K+), out of the cell, or the influx of negatively charged ions, such as chloride (Cl-), into the cell. Repolarization is essential for resetting the cell’s excitability and preparing it for subsequent signaling events.
refractory period
The refractory period is a brief period of time following the generation of an action potential during which a neuron or muscle cell is temporarily unable to generate another action potential in response to a stimulus. It consists of two phases: the absolute refractory period, during which the cell is completely incapable of generating another action potential regardless of the strength of the stimulus, and the relative refractory period, during which the cell requires a stronger-than-usual stimulus to generate an action potential. The refractory period ensures that action potentials propagate in a one-way fashion along the axon and allows for proper signaling and coordination within the nervous system.
signal amplification
Signal amplification is the process by which a small initial signal is greatly increased in magnitude during cellular signaling pathways. It involves a series of enzymatic reactions or molecular interactions that amplify the signal, leading to a robust cellular response. Signal amplification allows cells to efficiently detect and respond to low concentrations of signaling molecules or weak stimuli, ensuring accurate and effective signaling in biological systems.
signal integration
Signal integration is the process by which cells integrate multiple signals from different sources or pathways to generate a coordinated cellular response. It involves the integration of various extracellular signals, such as hormones, neurotransmitters, or growth factors, as well as intracellular signals derived from cellular metabolism or environmental cues. Signal integration allows cells to respond appropriately to complex and dynamic changes in their environment by integrating and processing diverse signals to regulate gene expression, cell growth, differentiation, and other cellular processes.
Describe chemical gradients and associated transport types.
Chemical Gradients:
- Difference in concentration of a substance across a space or membrane
- Drives movement of molecules from high concentration to low concentration
- Establishes a concentration gradient
Passive Transport:
- Movement of molecules down a concentration gradient (high to low)
- Does not require energy input
- Includes simple diffusion and facilitated diffusion
Active Transport:
- Movement of molecules against a concentration gradient (low to high)
- Requires energy input (ATP)
- Includes protein pumps and transporters
Simple Diffusion:
- Net movement of molecules from high to low concentration
- Follows concentration gradient
- Rate depends on surface area, distance, temperature, etc.
Facilitated Diffusion:
- Diffusion of molecules through protein channels/carriers
- Increases rate of diffusion
- Exhibits saturation kinetics
Osmosis:
- Diffusion of water molecules across a selectively permeable membrane
- Driven by concentration gradient of solutes
- Causes movement of water towards higher solute concentration
Understand that charged molecules move according to electrochemical gradient.
- Electrochemical gradient combines concentration gradient and electrical gradient
- Electrical gradient arises from separation of opposite charges across a membrane
- Charged molecules (ions) move in response to both chemical and electrical forces
Movement of Cations (Positive Ions):
- Driven down electrochemical gradient
- Move from higher concentration to lower concentration
- Also move from positive to negative electrical potential
Movement of Anions (Negative Ions):
- Driven down electrochemical gradient
- Move from higher concentration to lower concentration
- Also move from negative to positive electrical potential
Importance of Electrochemical Gradients:
- Establishes resting membrane potential in cells
- Provides energy for secondary active transport
- Involved in nerve impulse conduction
- Crucial for muscle contraction and relaxation
Sodium-Potassium Pump:
- Actively transports Na+ out and K+ into the cell
- Establishes ionic concentration gradients
- Creates electrical gradient (membrane potential)
- Requires ATP energy input
Describe membrane potential, polarization, and depolarization.
Membrane Potential:
- Voltage difference across a cell membrane due to uneven ionic distribution
- Typically -60 to -90 mV inside the cell relative to outside
- Established by sodium-potassium pump and ion channel permeabilities
Polarization:
- Increase in the membrane potential, making it more negative inside
- Caused by opening of potassium channels, allowing K+ efflux
- Hyperpolarizes the cell, making it harder to depolarize
Depolarization:
- Decrease in the membrane potential, making it less negative inside
- Caused by opening of sodium channels, allowing Na+ influx
- If depolarization is large enough, it triggers an action potential
- Sodium channels then inactivate, and potassium channels open to repolarize
Action Potential:
- Rapid depolarization followed by repolarization of the membrane
- Triggered when depolarization reaches threshold potential
- Propagated along excitable cells like neurons and muscle fibers
- Basis of electrical signaling in the nervous system
Refractory Period:
- Brief period after an action potential when another cannot be generated
- Allows sodium channels to reset before the next depolarization
Describe the parts of a neuron cell and a synapse.
Neuron Cell:
- Cell body (soma) - contains nucleus and organelles
- Dendrites - branched projections that receive signals
- Axon - long projection that transmits signals
- Axon terminals - end of axon that forms synapses
- Myelin sheath - insulating layer around axon for faster signal conduction
Synapse:
- Junction between axon terminal of one neuron and dendrite/soma of another
- Allows signals to be passed from one neuron to the next
Presynaptic Terminal:
- Axon terminal of the signal-sending neuron
- Contains synaptic vesicles filled with neurotransmitters
Synaptic Cleft:
- Narrow gap between pre and postsynaptic neurons
- Neurotransmitters diffuse across this space
Postsynaptic Membrane:
- Dendrite/soma membrane of the signal-receiving neuron
- Has neurotransmitter receptors
Excitatory Synapse:
- Neurotransmitters depolarize/excite the postsynaptic neuron
Inhibitory Synapse:
- Neurotransmitters hyperpolarize/inhibit the postsynaptic neuron
Describe the steps in neuronal signaling
- Resting Potential
- Neuronal membrane is polarized with negative charge inside and positive outside
- Maintained by sodium-potassium pump
- Action Potential Generation
- Depolarization opens sodium channels, allowing sodium influx
- Membrane potential becomes positive (action potential)
- Sodium channels inactivate and potassium channels open
- Potassium efflux restores negative resting potential
- Propagation of Action Potential
- Action potential propagates down axon as wave of depolarization
- Enabled by voltage-gated sodium and potassium channels
- Synaptic Transmission
- Action potential reaches axon terminal
- Calcium influx triggers neurotransmitter release
- Neurotransmitters bind to receptors on postsynaptic cell
- Excitatory or inhibitory postsynaptic potentials generated
- Integration of Signals
- Postsynaptic potentials summate at trigger zone
- If threshold reached, new action potential generated
- Allows signal propagation to next neuron
Apply electrochemical gradients, membrane potential, and ion transport to producing
an action potential in neuronal signaling
a) Describe ligand-gated vs. voltage-gated ion channels
a) Ligand-gated vs voltage-gated ion channels:
Ligand-gated ion channels:
- Opened/closed by binding of specific ligand (neurotransmitter)
- Allow ions to flow down electrochemical gradient
- Found at chemical synapses on postsynaptic membrane
- Example: Acetylcholine opens sodium channels at neuromuscular junction
Voltage-gated ion channels:
- Opened/closed by changes in membrane potential
- Sodium channels open with depolarization, allowing sodium influx
- Potassium channels open after sodium channels inactivate, allowing potassium efflux
- Found along axons and at axon terminals
- Allow action potential propagation and neurotransmitter release
b) Producing an action potential:
- Resting membrane potential established by electrochemical gradients (high K+ outside, high Na+/Anions inside)
- Stimulus from neurotransmitter or sensory input depolarizes segment of membrane
- If depolarization exceeds threshold, voltage-gated Na+ channels open
- Na+ rushes in down electrochemical gradient, reversing membrane polarity
- This regenerating inward current causes action potential to propagate
- Na+ channels inactivate, K+ channels open, allowing K+ efflux to restore negative resting potential
- Refractory period before another action potential can be generated
Connect action potential to signaling basics
- Resting Membrane Potential
- Established by electrochemical gradients (high K+ outside, high Na+/Anions inside)
- Maintained by sodium-potassium pump
- Sets the baseline for action potential generation
- Stimulus/Depolarization
- Neurotransmitters binding to ligand-gated channels or sensory input depolarizes membrane segment
- This brings the membrane potential closer to threshold for action potential
- Action Potential Generation
- If depolarization exceeds threshold, voltage-gated Na+ channels open
- Na+ rushes in down electrochemical gradient, reversing polarity
- Regenerating inward current causes action potential to propagate
- Propagation of Action Potential
- Wave of depolarization travels due to sequential opening of voltage-gated Na+/K+ channels
- Allows signal to be transmitted long distances along axon
- Synaptic Transmission
- Action potential arrives at axon terminal
- Depolarization opens voltage-gated Ca2+ channels
- Ca2+ influx triggers neurotransmitter release into synaptic cleft
- Neurotransmitters bind to ligand-gated channels on postsynaptic cell
- Integration of Signals
- Neurotransmitters generate excitatory or inhibitory postsynaptic potentials
- These are integrated at trigger zone on postsynaptic neuron
- If threshold is reached, a new action potential is generated
So the action potential results from electrochemical gradients and selective ionic movements through voltage/ligand-gated channels to transmit signals between neurons.
Understand how to read an action potential trace and what different parts of the peak
reflect in the cell and what they mean.
Resting Potential (Baseline)
- Represents resting membrane potential
- Due to unequal distribution of ions across membrane
Depolarization (Upstroke)
- Rapid upward deflection
- Caused by opening of voltage-gated Na+ channels
- Allows Na+ influx down electrochemical gradient
- Reverses membrane polarity
Peak/Overshoot
- Peak goes slightly positive
- Due to rapid, massive Na+ influx
Repolarization
- Downward slope after peak
- Na+ channels inactivate
- Voltage-gated K+ channels open
- K+ efflux restores negative charge inside
Undershoot/Hyperpolarization
- Membrane potential goes transiently more negative than rest
- Due to continued K+ efflux after Na+ channels close
Return to Resting Potential
- K+ channels close
- Resting ionic gradients re-established by Na+/K+ pump
Refractory Period
- Cannot generate new action potential until ionic gradients restored
- Ensures one-way conduction down axon
So the shape reflects the sequential opening/closing of voltage-gated channels and movement of specific ions to generate, propagate and terminate the action potential signal.
Describe the steps in G-protein coupled receptor (GPCR) signaling and recognize general
steps of signaling
- Ligand Binding
- Extracellular ligand (hormone, neurotransmitter, etc.) binds to GPCR - GPCR Activation
- Binding causes conformational change in GPCR
- Exposes binding site for G-protein on intracellular side - G-Protein Activation
- GPCR acts as a guanine nucleotide exchange factor
- Catalyzes exchange of GDP for GTP on G-protein α subunit
- Causes dissociation of α subunit from βγ subunits - Effector Enzyme Regulation
- GTP-bound α subunit and/or βγ subunits regulate effector enzymes
- e.g. Adenylyl cyclase, phospholipase C, ion channels - Second Messenger Production
- Effector enzymes produce second messengers
- e.g. cAMP, IP3, DAG, Ca2+ - Cellular Responses
- Second messengers trigger downstream effects
- e.g. Protein phosphorylation, gene expression, secretion - Signal Termination
- GTPase activity hydrolyzes GTP to GDP on α subunit
- Reassociation of α-GDP with βγ subunits
- GPCR is reset by phosphorylation or endocytosis
The general pattern is:
1) Extracellular signal
2) GPCR activation
3) G-protein activation
4) Effector regulation
5) Second messenger production
6) Amplified cellular responses
Apply GPCR signaling to neuromodulation
- Neurotransmitter/Neuromodulator Release
- Neurotransmitters (e.g. dopamine, serotonin) and neuromodulators (e.g. endocannabinoids, opioid peptides) are released from presynaptic terminals. - Binding to GPCRs on Neurons
- These ligands bind to specific metabotropic GPCRs on postsynaptic neurons and nearby neurons/glia. - G-Protein Activation
- GPCRs activate specific G-protein subtypes (Gs, Gi/o, Gq/11) on the intracellular side. - Regulation of Effectors
- Activated G-protein subunits modulate effector enzymes and ion channels:
- Adenylyl cyclase regulates cAMP levels
- Phospholipase C produces IP3 and DAG
- Ion channels control neuronal excitability - Cellular Responses
- Second messengers like cAMP, Ca2+, DAG trigger downstream effects:
- Modulation of synaptic strength (LTP, LTD)
- Changes in gene expression
- Regulation of neurotransmitter release
- Altered neuronal firing patterns
By activating specific GPCR pathways, neuromodulators can finely tune synaptic plasticity, neuronal integration, and circuit activity over diverse temporal and spatial scales in the brain.
Describe and understand examples of signal amplification and signal integration
Signal Amplification:
- This refers to mechanisms that amplify the initial signal, allowing a small stimulus to trigger a larger response.
- It provides sensitivity and regulation to signaling pathways.
Examples:
1) G-protein coupled receptors (GPCRs)
- One activated GPCR can activate multiple G-proteins
- Each G-protein can then modulate many effector enzymes/channels
- Amplifying effect of 1 ligand into many second messengers
2) Enzymatic Amplification
- Enzymes like adenylyl cyclase convert many ATP into cAMP molecules
- Each cAMP can activate protein kinases to phosphorylate multiple substrates
3) Calcium-Induced Calcium Release
- Small Ca2+ influx induces much larger release from ER stores
- Amplifying cytosolic Ca2+ signal
Signal Integration:
- This refers to the convergence and processing of multiple signals into an integrated cellular response.
- It allows cells to interpret complex environmental information.
Examples:
1) Neuronal Integration
- Synaptic inputs generate excitatory or inhibitory postsynaptic potentials
- These are integrated at trigger zones
- If the sum exceeds threshold, an action potential is produced
2) Transcription Factor Convergence
- Multiple signaling pathways activate different transcription factors
- These bind to regulatory regions of genes
- Integrated effect on specific gene expression patterns
3) Checkpoints in Cell Cycle
- Different external/internal signals act as GO or STOP signals
- These are integrated at cell cycle checkpoints
- Allowing appropriate progression or arrest of cell division
So amplification spreads signals while integration processes and resolves multiple incoming signals appropriately for a specific cellular response.
Amplification and Integration are principles found in virtually all types of receptor
signaling – we just learned it here – but the end of class problems ask you to recognize it
in previous types of receptors you learned.
Enzyme-Linked Receptors:
- Amplification via enzymatic activity converting many substrate molecules
- e.g. Receptor tyrosine kinases activating multiple downstream kinases
Ion Channel-Linked Receptors:
- Amplification by allowing influx/efflux of many ions down electrochemical gradients
- Integration of multiple ligand-gated channels at the neuronal trigger zone
Intracellular Receptors:
- Amplification when activated nuclear receptors regulate transcription of multiple genes
- Integration of signals from different lipophilic hormones on gene expression patterns
Even in simple ligand-gated ion channels, there is amplification when a single neurotransmitter opens a channel permitting many ions to flow.
The recurring theme is that cells use amplifying steps and integrating nodes to transduce small initial signals into larger, specific functional responses in virtually every receptor system.
You’re correct that recognizing these overarching principles in the various signaling mechanisms we’ve learned is likely an emphasis in the end of class problems. Thanks for the helpful reminder!
Innate immune response
The innate immune response is the body’s initial defense against pathogens, using non-specific mechanisms like inflammation and phagocytosis to quickly neutralize invaders.
Adaptive immune response
The adaptive immune response is the body’s targeted defense against specific pathogens, involving the recognition of unique antigens by specialized immune cells and the generation of antigen-specific responses, including the production of antibodies and the activation of T cells, to eliminate the invaders and establish immunological memory.
Pattern Recognition Receptor
Pattern recognition receptors (PRRs) are specialized proteins expressed by cells of the innate immune system that recognize conserved molecular patterns associated with pathogens, known as pathogen-associated molecular patterns (PAMPs), or with damaged cells, known as damage-associated molecular patterns (DAMPs). PRRs play a crucial role in initiating the innate immune response by detecting the presence of pathogens or danger signals and activating downstream signaling pathways that lead to the production of inflammatory cytokines, antimicrobial peptides, and other effector molecules to eliminate the threat.
Antigen
An antigen is any molecule or substance that can be recognized by the immune system as foreign or non-self, triggering an immune response. Antigens can be proteins, carbohydrates, lipids, or nucleic acids found on the surface of pathogens, such as bacteria, viruses, or parasites, as well as on the surface of transplanted tissues or cells. When the immune system encounters antigens, specialized immune cells, such as B cells and T cells, recognize and respond to them by generating antigen-specific immune responses, including the production of antibodies by B cells and the activation of cytotoxic T cells to eliminate the antigen-bearing cells.
Macrophage cell
A macrophage is a type of immune cell belonging to the innate immune system. It is derived from monocytes, a type of white blood cell, and is found in various tissues throughout the body, where it plays a critical role in immune defense, inflammation, and tissue homeostasis. Macrophages are known for their phagocytic activity, meaning they can engulf and digest pathogens, dead cells, and cellular debris. Additionally, macrophages act as antigen-presenting cells, displaying antigens derived from engulfed pathogens to activate other immune cells, such as T cells. They also produce inflammatory cytokines and chemokines to recruit other immune cells to sites of infection or injury. Macrophages are versatile cells with diverse functions in immune surveillance, tissue repair, and immune regulation.
Cytokine
Cytokines are small proteins secreted by cells that act as signaling molecules to regulate immune responses and inflammation.
Dendritic cell
Dendritic cells are a type of immune cell that plays a key role in initiating and regulating immune responses by presenting antigens to other immune cells, such as T cells.
plasma B cell
A plasma B cell is a specialized type of white blood cell that produces and secretes antibodies, which are proteins that help the immune system identify and neutralize pathogens such as bacteria and viruses.
Antigen Presenting Cell
An antigen-presenting cell (APC) is a type of immune cell that displays antigens on its surface to activate other immune cells, such as T cells. This process is crucial for initiating and regulating immune responses against pathogens or abnormal cells. Examples of APCs include dendritic cells, macrophages, and B cells.
T cell
A T cell is a type of white blood cell that plays a central role in the adaptive immune response. T cells are responsible for recognizing specific antigens presented by antigen-presenting cells (such as dendritic cells) and activating other immune cells to eliminate pathogens or abnormal cells. There are several types of T cells, including helper T cells, cytotoxic T cells, and regulatory T cells, each with different functions in the immune system.
Cytotoxic T cell
Cytotoxic T cells, also known as CD8+ T cells, are a type of T lymphocyte that directly kills infected or abnormal cells. They recognize specific antigens presented on the surface of infected or cancerous cells and induce cell death through the release of cytotoxic molecules, such as perforin and granzymes. Cytotoxic T cells play a crucial role in the adaptive immune response against viruses, intracellular bacteria, and cancer cells.
T helper cell
T helper cells, also known as CD4+ T cells, are a type of T lymphocyte that coordinates the immune response by activating and directing other immune cells, such as B cells and cytotoxic T cells. They recognize specific antigens presented by antigen-presenting cells and release cytokines to regulate the immune response. T helper cells play a crucial role in both the activation of the immune system against pathogens and the regulation of immune tolerance to prevent autoimmune reactions.
co-stimulation
Co-stimulation refers to the process in which additional signals, beyond the recognition of antigen alone, are required to fully activate T cells during an immune response. These signals are provided by molecules on the surface of antigen-presenting cells and help ensure that T cells respond appropriately to pathogens while avoiding unnecessary activation. Co-stimulation is essential for the proper regulation of immune responses and the development of effective immunity.
antibody
An antibody, also known as an immunoglobulin, is a protein produced by plasma B cells in response to the presence of specific antigens, such as those found on pathogens like bacteria or viruses. Antibodies bind to antigens with high specificity, marking them for destruction by other components of the immune system or neutralizing their harmful effects directly. Antibodies play a critical role in immune defense, including in immune responses to infections, vaccinations, and maintaining immune tolerance.
B cell
A B cell is a type of white blood cell that plays a central role in the adaptive immune system. B cells are primarily responsible for producing antibodies, which are proteins that recognize and bind to specific antigens, such as those on pathogens like bacteria or viruses. When activated by antigens, B cells differentiate into plasma cells, which secrete large amounts of antibodies, and memory cells, which provide long-term immunity by “remembering” previous encounters with specific antigens. B cells are essential for the body’s defense against infections and for the effectiveness of vaccines.
memory B cells
Memory B cells are a specialized type of B lymphocyte that forms after an initial exposure to an antigen, such as during an infection or vaccination. Unlike plasma cells, which produce antibodies immediately, memory B cells persist in the body for a long time, “remembering” the specific antigen they encountered. If the same antigen is encountered again, memory B cells can quickly proliferate and differentiate into plasma cells, producing a rapid and robust secondary immune response. Memory B cells play a crucial role in providing long-term immunity to previously encountered pathogens and in the effectiveness of vaccines.
Be able to describe how innate immunity works including the 4 parts that make up the
system.
* Barrier, sensing, communication, destruction
- Barrier Defenses
- Physical and chemical barriers that prevent entry of pathogens
- Examples: Skin, mucous membranes, stomach acid, enzymes in secretions - Pathogen Sensing
- Pattern recognition receptors (PRRs) detect conserved molecular patterns on pathogens
- Examples: Toll-like receptors, NOD-like receptors, RIG-I-like receptors - Communication
- After sensing pathogens, innate cells communicate via signaling molecules
- Examples: Cytokines (interferons, interleukins), chemokines, complement proteins
- Recruits and activates other innate immune cells, signals adaptive immunity - Destruction
- Activated innate cells use various mechanisms to destroy pathogens
- Examples: Phagocytosis, inflammation, antimicrobial peptides, cytotoxic enzymes
- Innate immune cells: Macrophages, neutrophils, dendritic cells, mast cells, NK cells
The four concerted parts allow the innate system to rapidly detect and respond to invading microbes in a coordinatedway before adaptive immunity can be activated.
Be able to describe how adaptive immunity works
* Antigen presentation, T cell activation, B cell activation, Antibodies, Memory
Antigen Presentation:
- Dendritic cells and macrophages process and present antigenic peptides on MHC molecules
- Peptide:MHC complexes are recognized by T cell receptors on naive T cells
T Cell Activation:
- Antigen presentation, plus co-stimulatory signals, activates naive CD4+ helper T cells
- Helper T cells secrete cytokines to activate other immune cells
B Cell Activation:
- Activated helper T cells bind to B cells presenting same antigen
- Helper T cell cytokines stimulate B cell proliferation and antibody production
Antibody Production:
- Activated B cells differentiate into antibody-secreting plasma cells
- Secreted antibodies bind to and neutralize/mark pathogens for destruction
Memory:
- Some activated T and B cells become long-lived memory cells
- Allow faster and stronger response if exposed to same antigen in future
Key Features:
- Antigen specificity via diverse T cell receptors and antibodies
- Primary vs secondary (memory) response
- Central role of antigen presentation to T cells
- Cooperative interaction between T cells and B cells
- Enables pathogen elimination and long-lasting protection
The adaptive immune response takes days to weeks to develop, but provides highly specific and lasting immunity upon re-exposure.
Compare and contrast innate vs. adaptive
Here’s a comparison of the key differences between innate and adaptive immunity:
Innate Immunity:
- First line of defense against pathogens
- Present from birth (inherited)
- Rapid response (hours)
- Recognition of generic pathogen patterns
- No immunological memory
- Main components: Physical barriers, phagocytic cells, NK cells, antimicrobial proteins
Adaptive Immunity:
- Develops later after exposure/infection
- Highly specific for particular pathogens
- Delayed response (days/weeks)
- Immunological memory for future exposures
- Main components: T lymphocytes, B lymphocytes, antibodies
Innate vs Adaptive:
- Innate is non-specific, adaptive is pathogen-specific
- Innate has no memory, adaptive has immunological memory
- Innate is immediate, adaptive is delayed
- Innate recognizes conserved molecular patterns, adaptive recognizes specific antigens
- Innate is inherited, adaptive develops during one’s lifetime
- Both are required for complete immune defense
While innate immunity forms the initial rapid frontline, the adaptive system provides the targeted response and long-lasting protective immunity. They work cooperatively, with innate mechanisms also enhancing activation of the adaptive response.
Be able to describe immune receptor signaling and apply cell signaling concepts.
Sure, here’s how immune receptor signaling works by applying the general cell signaling concepts we’ve learned:
Immune Receptor Signaling:
1) Ligand Binding
- Pattern recognition receptors (PRRs) like Toll-like receptors bind pathogen-associated molecular patterns (PAMPs)
- Antigen receptors on B and T cells bind specific antigen epitopes
2) Receptor Oligomerization/Clustering
- Ligand binding causes receptor subunits to oligomerize/cluster in the membrane
- This brings associated molecules into proximity
3) Activation of Signaling Cascades
- Oligomerized receptors recruit intracellular signaling molecules/enzymes
- Initiates signaling cascades e.g. IRAK/TRAF for TLRs, Src/Syk for antigen receptors
4) Second Messengers
- Signaling cascades activate second messengers like Ca2+, DAG, IP3
- These amplify and spread the signal to multiple downstream pathways
5) Transcriptional Responses
- Activated signaling pathways lead to nuclear translocation of transcription factors
- Induces gene expression programs for immune responses
6) Functional Responses
- Gene expression leads to cytokine production, proliferation, differentiation
- Allows pathogen clearance, antigen presentation, antibody production
7) Negative Regulation
- Inhibitory receptors, ubiquitination, phosphatases terminate signaling
- Prevent excessive inflammatory responses
So immune receptors utilize common concepts like clustering, signal amplification via cascades/second messengers, transcriptional regulation, and negative feedback - tailored for specific immune functions.
CRISPR
- CRISPR is a revolutionary genome editing technology that allows precise modification of DNA sequences.
- It is derived from a natural defense mechanism in bacteria, which uses CRISPR to detect and cut foreign genetic material from viruses.
- The CRISPR system consists of two key components:
1) A Cas9 enzyme that acts as molecular scissors to cut DNA strands
2) A guide RNA molecule that binds to and guides the Cas9 enzyme to the specific target DNA sequence - By designing the guide RNA to match a desired DNA sequence, the Cas9 enzyme can be programmed to cut at that exact genomic location.
- After the DNA is cut, scientists can remove, add, or alter specific genetic sequences through natural cellular repair mechanisms.
- CRISPR allows gene editing and genetic engineering with unprecedented ease, efficiency, and precision compared to older techniques.
- Applications include correcting genetic defects, treating diseases, improving crops, eliminating pathogens, basic research studies, and more.
- Ethical concerns have been raised about the potential misuse of CRISPR for germline editing of human embryos to create genetically modified humans.
- Despite concerns, CRISPR is a powerful tool driving new therapeutic and biotechnology innovations in medicine, agriculture, and many other fields.
Cas9
Cas9 is a protein derived from bacterial immune systems, particularly from the CRISPR-Cas system of bacteria such as Streptococcus pyogenes. It is used as a tool in genetic engineering and gene editing due to its ability to precisely target and cut specific sequences of DNA. Cas9 is often combined with a guide RNA molecule to guide it to the desired DNA target site, where it induces a double-strand break that can be repaired by cellular mechanisms, allowing for precise modifications to the genetic code.
guide RNA
Guide RNA (gRNA) is a synthetic or naturally occurring RNA molecule used in the CRISPR-Cas gene editing system to guide the Cas nuclease (such as Cas9) to a specific target sequence within a DNA molecule. The guide RNA contains a sequence that is complementary to the target DNA sequence, allowing it to bind to the DNA and direct the Cas nuclease to make a precise cut at that location. By designing custom guide RNAs, researchers can target specific genes for modification, deletion, or other genetic alterations with high precision.
morphogen
A morphogen is a signaling molecule that regulates the pattern formation and development of tissues and organs during embryonic development. Morphogens are secreted by cells and diffuse through tissues, creating concentration gradients that provide positional information to neighboring cells. This information helps determine the fate and differentiation of cells, leading to the formation of complex structures with distinct cell types and functions. Morphogens play a crucial role in processes such as embryogenesis, tissue regeneration, and organ development.
phage
A phage, short for bacteriophage, is a virus that infects and replicates within bacteria. Phages are composed of a protein coat enclosing genetic material, either DNA or RNA. Upon infecting a bacterial cell, the phage injects its genetic material, hijacking the bacterial machinery to produce more phage particles. These newly produced phages can then infect other bacterial cells, continuing the cycle. Phages have been extensively studied for their potential use in various applications, including bacterial control in agriculture, food safety, and as tools in molecular biology and biotechnology.
nuclease (Cas9 is nuclease – enzyme that cuts nucleotides – “scissors”)
A nuclease is an enzyme that cleaves nucleic acids, such as DNA or RNA, by breaking the phosphodiester bonds between nucleotides. Cas9, the enzyme commonly used in the CRISPR-Cas9 gene editing system, is a nuclease that functions as molecular “scissors” to cut DNA at specific target sequences. This ability to precisely cleave DNA makes Cas9 a powerful tool for making targeted changes to the genetic code.
repair template
A repair template is a strand of DNA or RNA used in gene editing techniques, such as CRISPR-Cas9, to introduce specific changes to a target gene. After the Cas nuclease, like Cas9, creates a double-strand break in the target DNA, a repair template containing the desired genetic sequence can be introduced into the cell. The cell’s repair machinery then uses this template to repair the break, incorporating the desired sequence into the genome. Repair templates are crucial for introducing precise changes, such as gene knockouts, insertions, or substitutions, into the genome of an organism.
Describe how CRISPR-Cas9 functions like an adaptive immunity in bacteria – memory and
specific to pathogen infected by
Exposure and Memory Formation:
- When a bacterium is infected by a virus (bacteriophage), it can incorporate short fragments of the viral DNA into its own CRISPR locus.
- These viral DNA snippets act as “memories” or genetic records of past viral infections.
CRISPR RNA (crRNA) Production:
- The CRISPR locus is transcribed into short crRNA molecules, each containing a 20nt sequence complementary to a viral sequence.
- This is analogous to the generation of diverse antibodies or T cell receptors in adaptive immunity.
Guide RNA Loading:
- The crRNA associates with a Cas9 enzyme (or other Cas protein) to form a RNA-protein complex.
- The crRNA acts as a guide molecule to direct the Cas9 to the matching viral DNA sequence, similar to antibodies guiding immune cells.
Target Recognition and Destruction:
- If the bacterium encounters that virus again, the crRNA will bind to the matching viral DNA sequence.
- The Cas9 is then able to precisely cut and degrade the viral DNA, neutralizing the virus.
- This is akin to antibodies marking pathogens for destruction by immune cells.
Acquisition of New Memories:
- During subsequent viral infections, new viral sequences can be acquired and added to the CRISPR locus.
- This allows adaptation and immunological memory against a wider range of viruses.
So like the adaptive immune system, CRISPR provides bacteria a way to:
1) Record memories of previous pathogens (viral DNA)
2) Generate diverse, pathogen-specific targeting molecules (crRNAs)
3) Precisely detect and destroy those specific pathogens upon re-exposure
This confers adaptive, inherited immunity that provides protection for the bacterial population.
Describe how CRISPR-Cas9 system can be used to as a gene editing tool – know components
required, their names, and their function/role
1) Cas9 Nuclease Enzyme
- Cas9 is an endonuclease enzyme that can cut double-stranded DNA.
- It’s the molecular “scissors” that creates the double-strand break in the target DNA.
- The Cas9 from Streptococcus pyogenes is commonly used for gene editing.
2) Single Guide RNA (sgRNA)
- A synthetic RNA molecule with two components:
- crRNA: ~20 nucleotides complementary to target DNA sequence
- tracrRNA: Binds and activates the Cas9 nuclease
- The sgRNA binds to the target sequence and recruits/guides Cas9 there.
3) PAM Sequence
- Protospacer Adjacent Motif - a short DNA sequence (NGG) that flanks the target site.
- The PAM is recognized by Cas9 and required for its DNA binding/cutting.
4) Repair Mechanisms
- After Cas9 creates a double-strand break, cellular repair mechanisms are harnessed:
- Non-homologous end joining (NHEJ) to disrupt gene
- Homology-directed repair (HDR) with donor DNA to introduce desired edits
The steps are:
1) Design and synthesize sgRNA to target a specific genomic sequence
2) Introduce sgRNA and Cas9 into cells
3) sgRNA guides Cas9 to PAM site and binds target DNA
4) Cas9 creates double-strand break at target locus
5) Cellular repair pathways are hijacked to make desired gene edits
This programmable, RNA-guided DNA targeting and cutting allows efficient and multiplexed editing of genes or whole genomic loci in diverse cells and organisms.
