Chapter 5: Cell Signaling in Physiology Flashcards
5.1 Receptors
There are several classes of chemical messengers that can communicate a signal to one another. The cell receiving the signal must be able to detect the signals presence. Once a cell detects the signal, a mechanism is required to transduce the signal into a physiologically meaningful response. EX: cell division for growth signals.
The first step in the action of an intercellular chemical messenger is the binding of the messenger to specific target-cell proteins called RECEPTORS.
Chemical signal is a LIGAND and RECEPTOR has BINDING SITE for LIGAND. Binding causes conformational change in RECEPTOR that activates it and elicits a chemical response called SIGNAL TRANSDUCTION. Causes stimulus and response.
LIGAND = chemical messenger
Chemical messengers (LIGANDS) bind to specific target-cell proteins known as RECEPTORS.
Two types of LIGANDS:
1. water-soluble- bind to receptors located at the plasma membrane
2. lipid-soluble- bind to an intracellular receptor
Remember: plasma membrane structure consists of two layers of phospholipids.
head of the phospholipid → hydrophilic, lipophobic, has partially negative charge that attracts water
tail of phospholipid → hydrophobic, lipophilic, is nonpolar mostly (doesn’t have charge) so it is not attacted to charges on water
example of phospholipid bilayer:
o= =o
o= =o
o= =o
o= =o
5.1 Receptors, Types of Receptors
Proteins or glycoproteins located either in the cell’s membrane or inside the cell, either in the cytosol or the nucleus bind intercellular messengers.
PLASMA MEMBRANE RECEPTORS
- These can be integral proteins that allow intracellular and extracellular communications and have an active intracellular side that causes changes within the cell
- transmembrane receptors with hydrophobic portions inside and hydrophilic portions outside
- incoming messengers bind to extracellular receptors and the internal region plays along in signal transduction
INTRACELLULAR RECEPTORS
- not located in membrane, found either in cytosol or nucleus
- very different structure from membrane receptors
- segment that binds to messenger and segment that is regulatory site and segment that binds to DNA
- transduce signals with interactions with genes
5.1 Receptors, Interactions Between Receptors and Ligands
SPECIFICITY
- the ability of a receptor to bind only one type of a limited number of structurally related chemical messengers; only cells that express the right receptor can bind to a particular messenger
- better fit between ligand and receptor
- ligand that fits in receptor will cause conformational change
- different cell types express different types of receptors; a single cell can express multiple receptor types; binding elicits response and different receptors will not give response
- lock-and-key fit
a. receptor = lock, ligand = key
- a single type of receptor can be used to produce different responses to the same chemical messenger in different cell types (ex: norepinephrine)
AFFINITY
- the strength with which a chemical messenger binds to its receptor
- high-ligand receptor affinity → binds quickly, more bound, will bind at lower concentrations
- low-ligand receptor affinity → less attractive force, binds slower and less, will not bind as much at lower concentrations
- COMPETITORS (IE DRUGS)- the ability of different molecules to compete with a ligand for binding to its receptor; competitors generally are similar in structure with the natural ligand; complete receptors, reduce the amount of natural ligand binding (ex: progesterone’s low affinity can still bind to and activate testosterone receptor)
- affinity has implications for drug action
a. AGONISTS- drug that mimics a messenger’s actions by binding to and activating the messenger’s receptor
b. ANTAGONISTS- drug that inhibits a messenger’s actions by binding to an inhibiting a messenger’s receptor
SATURATION
- the degree to which receptors are occupied by messengers; if all are occupied, receptors are fully saturated; if half are occupied, receptors are 50% saturated, and so on
- a cell’s response to a messenger increases as the extracellular concentration of substrate increases because # of receptors occupied increases, but there is an upper limit, and chemical reaction will slow down once most or all receptors get filled by substrate
COMPETITION
- COMPETITION- the ability of different molecules to compete with a ligand for binding to its receptor; competitors generally are similar in structure with the natural ligand;
- complete receptors, reduce the amount of natural ligand binding (ex: progesterone’s low affinity can still bind to and activate testosterone receptor)
a. AGONISTS- drug that mimics a messenger’s actions by binding to and activating the messenger’s receptor
b. ANTAGONISTS- drug that inhibits a messenger’s actions by binding to an inhibiting a messenger’s receptor
5.1 Receptors, Regulation of Receptors
Receptors are subject to physiological regulation. The number of receptors are cell has, or the affinity of the receptors for their specific messengers can be regulated.
RECEPTORS are subject to physiological regulation by their own messengers
a. UP-REGULATION- the numbers of receptors are increased by their messenger; may result in INCREASED sensitivity to the messenger; cells exposed for prolonged periods of time to low messenger concentrations may have come to have increased receptor presence, and causing an increased sensitivity to the messenger (↑ 3 of receptors for ligands = ↑ likelihood bonding will occur); intracellular vesicles with receptors proteins within may fuse with membrane to increase presence of receptors and decrease sensitivity; b. DOWN-REGULATION- the numbers of receptors are decreased by their messenger via the process of INTERNALIZATION; when high extracellular concentration of messenger is maintained, number of receptors decreases; compensates for chronically elevated extracellular concentrations of a messenger; reduces cells responsiveness to frequent or intense stimulation by messenger and causes overall negative feedback mechanism; INTERNALIZATION indicates that the messenger-receptor complex is taken into the cell by receptor-mediated endocytosis which increases rate of receptor degradation in cell
5.2 Signal Transduction Pathways
The binding of a messenger to its receptor causes a conformational change (tertiary structure) of the receptor. This is known as RECEPTOR ACTIVATION, and it is the cell’s initial step leading to the cell’s responses to the messenger.
Cellular responses take the form of changes in:
1. the permeability, transport properties, or electrical state of the plasma membrane
2. metabolism
3. secretory activity
4. rate of proliferation and differentiation
5. contractile and other activities
SIGNAL TRANSDUCTION PATHWAYS are the diverse sequences of events that link receptor activation to cellular responses. They differ between lipid-soluble messengers and water-soluble messengers.
- Pathways may be active simultaneously in a single cell, undergoing complex interactions
a. a single first messenger may trigger changes in the activity of more than one pathway
b. many different first messenger may simultaneously influence a cell - “crosstalk” can occur at one or more levels among the various signal transduction pathways
PROTEIN KINASE: enzyme that phosphorylates other proteins by transferring a phosphate group to them from ATP; note: different proteins respond differently to phosphorylation → some are activated while others are inactivated
5.2 Signal Transduction Pathways, Pathways Initiated by Lipid-Soluble Messengers
LIPID-SOLUBLE MESSENGERS: bind to NUCLEAR RECEPTORS inside the target cell
- activated receptor acts in the nucleus as a transcription factor
- include hydrophobic substances such as steroids and thyroid hormone
- belongs to large family of intracellular receptors called NUCLEAR RECEPTORS that share similar structures and mechanisms of actions
- in most cases already reside in the nucleus but sometimes are inactive in cytosol and then migrate to nucleus when active
- almost all lipophilic change gene transcription (up-regulation)
- can up-regulate or down-regulate gene transcription
- takes time to see cell response (usually 20+ minutes), slow, but sustained response
messenger diffuses out of capillaries to interstitial fluid → diffuses across plasma membrane and nuclear envelope to go to nucleus and bind to receptor there → activated receptor functions are transcription factor → binds to DNA and produces mRNA → mRNA translated into proteins by ribosomes → increases presence of specific protein to get to ultimate goal of messenger
- bind to receptor in cytosol or nucleus
a. bind DNA
b. change transcription of genes
5.2 Signal Transduction Pathways, Pathways Initiated by Water-Soluble Messengers
WATER-SOLUBLE MESSENGERS: bind to four classes of receptors on the plasma membrane:
1. receptors that are also ligand-gated ion channels
a. ligand-binding → conformational change
→ opens ion channel
b. ion specific- usually 1-2 ions, limited by
size and charge
c. ions diffuse across membrane- net
direction determined by concentration
gradient and charge of ion
d. can change membrane potential of a cell!!
2. receptors that are also enzymes
a. most are tyrosine kinases (phosphorylate
tyrosine residues) but there is the
exception of guanylyl cyclase to catalyze
the formation of cyclic GMP which
creates a second messenger cascade
with cGMP-dependent protein kinase
b. binding changes the conformation of the
receptor → enzyme portion is activated
c. active kinase phosphorylates intracellular
proteins using ATP
d. sets off chain reaction to change cell’s
response
3. receptors that activated a cytosolic janus kinase associated with them
a. do not have intrinsic kinase activity- have
cytoplasmic kinases called janus kinases
(JAKs) associated with the receptor
b. ligand binding cause receptor
conformational change → activates JAK
c. active JAK → phosphorylates proteins
(transcription factors) → cell’s response
(protein synthesis)
4. receptors that interact with an associated plasma membrane G-PROTEIN (G-PROTEIN-COUPLED-RECEPTORS)
- activate intracellular signaling cascades that affect cell function
- receptors activate downstream mediators
a. can affect DNA transcription
b. also have many other effects in the cell - faster response, less sustained
- cannot diffuse through the membrane, so they bind to extracellular portions or receptor proteins in plasma membrane
REVIEW JANUS KINASES and tyrosine kinases
5.2 Signal Transduction Pathways, First Messengers and Second Messengers
FIRST MESSENGERS: the messengers that bind to protein receptors
- made and released in very small amounts
- can produce large cellular responses through signal amplification
SECOND MESSENGERS: substances generated in a cell by the actions of first messengers
- many more produced
- each phosphorylates many target enzymes
- each enzyme phosphorylates many final products
5.2 Signal Transduction Pathways, Major First Messenger Cascades, G-Coupled Receptors
- ligand binding
- receptor conformational change
- increased affinity of the alpha subunit for GTP
- alpha subunit dissociates from the beta and gamma subunits
- links up with either an ion channel or an enzyme
- leads to change in membrane potential or second messenger cascade, respectively
5.2 Signal Transduction Pathways, Major Second Messengers
Three examples:
1. Adenylyl cyclase and cyclic AMP
2. Phospholipase C, DAG, IP₃
3. Calcium-calmodulin
4. Guanylyl Cyclase and Cyclic GMP
5.2 Signal Transduction Pathways, Major Second Messengers, Cyclic GMP
GUANYLYL CYCLASE functions as both a receptor and as an enzyme
- catalyzes the formation of cyclic GMP (cGMP)
- cGMP is a SECOND MESSENGER
a. activates a protein kinase called cGMP-dependent protein kinase
b. this kinase phosphorylates specific proteins that then mediate the cell’s response
- Guanylyl cyclase can be a membrane-bound or cytosolic receptor
5.2 Signal Transduction Pathways, Major Second Messengers, Adenylyl Cyclase and Cyclic AMP
ADENYLYL CYCLASE: membrane enzyme that catalyzes the formation of the second messenger cAMP
- cAMP activates the intracellular cAMP-DEPENDENT PROTEIN KINASE, which phosphorylates proteins that mediate the cell’s responses to the first messenger
- activated cAMP-dependent protein kinase can phosphorylate many different proteins
a. activates some
b. inhibits others
- can turn on one pathway while turning off another
a. can turn on one pathway while turning off
another (eg glycogen)
1a. ligand binding activates g-protein coupled receptor
2a. alpha subunit binds GTP and activates adenylyl cyclase
3a. activated adenylyl cyclase converts ATP to cAMP
4a→b. cAMP activates cAMP-DEPENDENT PROTEIN KINASE A (PKA) which…
5b. phosphorylates protein targets in the cascade
6. cellular response is activated
- the second messenger response ends when cAMP PHOPHODIESTERASE breaks down cAMP to AMP
5.2 Signal Transduction Pathways, Major Second Messengers, Phospholipase C, DAG, and IP₃
PHOSPHOLIPASE C: plasma membrane enzyme that catalyzes the formation of second messengers DIACYLGLYCEROL (DAG) and INOSITOL TRIPHOSPHATE (IP₃)
- DAG activates PROTEIN KINASE C; IP₃ causes release of Ca²⁺ from the endoplasmic reticulum, thereby elevating cytosolic Ca²⁺
- Ca²⁺ is a widespread second messenger and activates regulatory molecules such as calmodulin
1a. G protein is called → activated by binding a first messenger
2a. activated then activated PHOSPHOLIPASE C (PLC)
3a. PLC catalyzes the breakdown of phosphatidylinositol biphosphate to DIAGLYCEROL (DAG) and INOSITOL TRIPHOSPHATE (IP₃)
IP₃
4b. binds to ligand-gated channels on the ER
5b. they open when bound to → increased cytosolic concentration
6b. increased binding continues the sequence of events leading to the cell’s response
7b. can activate some forms of protein kinase C, enhancing the effects of DAG
8b. IP₃ causes release of Ca²⁺ from the endoplasmic reticulum, thereby elevating cytosolic Ca²⁺
DAG
4c. activates PROTEIN KINASE C
5c. PKC phosphorylates a large number of other proteins
6c. leads to the cell’s response
5.2 Signal Transduction Pathways, Major Second Messengers, Calcium-Calmodulin and the calmodulin-dependent protein kinase system
1a. G protein is called → activated by binding a first messenger
2a. activated then activated PHOSPHOLIPASE C (PLC)
3a. PLC catalyzes the breakdown of phosphatidylinositol biphosphate to DIAGLYCEROL (DAG) and INOSITOL TRIPHOSPHATE (IP₃)
IP₃
4b. binds to ligand-gated channels on the ER
5b. they open when bound to → increased cytosolic concentration
6b. increased binding continues the sequence of events leading to the cell’s response
7b. can activate some forms of protein kinase C, enhancing the effects of DAG
8b. IP₃ causes release of Ca²⁺ from the endoplasmic reticulum, thereby elevating cytosolic Ca²⁺
Ca²⁺ is a widespread second messenger and activates regulatory molecules such as CALMODULIN.
1c. on binding with calcium, calmodulin changes shape
2c. calcium-calmodulin activates or inhibits a large variety of enzymes and other proteins (many are kinases)
3c. this leads to activation or inhibition of proteins involved in the cell’s ultimate responses
5.2 Signal Transduction Pathways, Other Messengers
EICOSANOIDS: derived from ARACHIDONIC ACID, and exert widespread intracellular and extracellular effects on cell activity
- examples include LEUKOTRIENES, PROSTAGLANDINS, and THROMBOXANES
- cessation of receptor activity occurs when the first-messenger molecule concentration decreases, or in the case of plasma membrane receptors, when the receptor is chemically altered or internalized
- EICOSANOIDS are from a family of molecules produced from arachidonic acid
- they include:
a. cyclic endoperoxides
b. prostglandins
c. thromboxanes
d. leukotrienes - they are generated in many kinds of cells in response to different types of extracellular signals
- stimulus binds to its receptor and activates PHOSPHOLIPASE A₂ (PLA₂)
2b. PLA₂ splits off arachidonic acid from the membrane phospholipids
3c. arachidonic acid →
a. cyclooxygenase (COX) → cyclic endoperoxides
→ prostaglandins (vascular actions,
inflammation) and thromboxanes blood
clotting and other vascular actions)
b. lipoxygenase → leukotrienes (mediate allergic
and inflammatory reactions)
