Signal Transduction, Membrane Receptors, Second Messengers, and Regulation of Gene Expression Flashcards
Antithrombotic drug that inhibits 💡cyclooxygenase-1 (COX1) and cyclooxygenase-2 (COX2)💡
ASPIRIN
Increase 💡cardiac contractility and 💡heart rate in patients with low blood pressure
β1-Agonists
💡Dilate bronchi and are used to treat 💡asthma and chronic obstructive lung disease.
β2-Agonists
Used to treat 💡hypertension, angina, cardiac arrhythmias, and congestive heart failure
β-adrenergic antagonists
An 💡antidepressant medication that 💡inhibits reuptake of the neurotransmitter 💡serotonin into the presynaptic cell
Fluoxetine (Prozac)
A 💡monoclonal antibody used to treat 💡metastatic breast cancer in women who overexpress 💡HER2/neu
Trastuzumab (Herceptin)
💡Monoclonal antibodies that are used to treat 💡metastatic colorectal cancer and 💡cancers of the head and neck.
These antibodies bind to and 💡inhibit the EGF receptor and thereby inhibit EGF-induced cell growth in cancer cells.
Cetuximab (Erbitux) and bevacizumab (Avastin)
Drugs that 💡inhibit cyclic guanosine monophosphate (cGMP)–specific phosphodiesterase type 5, prolong the 💡vasodilatory effects of nitric oxide and are used to treat 💡erectile dysfunction and pulmonary arterial hypertension
Sildenafil (Viagra), Tadalafil (Cialis), and Vardenafil (Levitra)
How Cells Communicate
💡💡 Ligand Receptor Signaling proteins Target proteins Effect
A signaling molecule (i.e., hormone or neurotransmitter) binds to a receptor, which may be in the plasma membrane, cytosol, or nucleus. Binding of ligand to a receptor activates intracellular signaling proteins, which interact with and regulate the activity of one or more target proteins to change cellular function. Signaling molecules regulate cell growth, division, and differentiation and influence cellular metabolism. In addition, they modulate the intracellular ionic composition by regulating the activity of ion channels and transport proteins. Signaling molecules also control cytoskeleton-associated events, including cell shape, division, and migration and cell-to-cell and cell-to-matrix adhesion
Signaling pathways are characterized by:
(1) multiple, hierarchical steps;
(2) amplification of the signal-receptor binding event, which magnifies the response;
(3) activation of multiple pathways and regulation of multiple cellular functions
(4) antagonism by constitutive and regulated feedback mechanisms,
Secretion of signaling molecules is?
Cell-type Specific
In which a 💡membrane-bound signaling molecule of one cell binds directly to a 💡plasma membrane receptor of another cell.
Important during development, in immune responses, and in cancer
Contact-Dependent Signaling
Are released by 💡one type of cell and 💡act on another type
Usually taken up and degraded by enzymes.
Ex. Enterochromaffin-like cells
PARACRINE SIGNALS
Involves the release of a molecule that affects the 💡same cell or other cells of the 💡same type
Occurs at 💡short distances
Example: Cancer cell, insulin release by the beta cells of the pancrease
Autocrine Signaling
💡Neurons transmit electrical signals along their axons and release neurotransmitters at synapses that affect the function of other neurons or cells that are distant from the neuron cell body
Synaptic Signaling
Are 💡hormones that are secreted into the blood and are widely dispersed in the body
Occurs over 💡long distances
Relatively 💡slow compared to the synaptic signaling
ENDOCRINE SIGNALS
Specialized junctions that allow intracellular signaling molecules, generally less than 1200 D in size, to diffuse from the cytoplasm of one cell to an 💡adjacent cell.
Gap Junctions
It regulates the 💡permeability of gap junctions
💡 C H Cyclic MP
Cytosolic Ca2+, H+
Cyclic adenosine monophophate (cAMP)
Membrane Potentials
All signaling molecules bind to specific receptors that act as (1)__, thereby converting a (2)__ into intracellular signals that affect cellular function.
💡💡
ST
LRBE
(1) SIGNAL TRANSDUCERS
(2) LIGAND-RECEPTOR BINDING EVENT
4 Basic Classes of Membrane Receptors
💡💡 L G E N
(1) ligand-gated ion channels,
(2) G protein–coupled receptors (GPCRs),
(3) enzyme-linked receptors,
(4) nuclear receptors
Mediate 💡direct and 💡rapid synaptic signaling between 💡electrically excitable cells
A membrane receptors that has direct and rapid synaptic signaling between electrically excitable cells.
This class of receptors transduces a 💡chemical signal into an 💡electrical signal, which elicits a response
Predominates in the nervous system mediating fast
excitatory or inhibitory neurotransmission.
Ligand-Gated Ion Channels/Ionotrophic
Or
Voltage-gate; Stretch- activated; and Temperature-gated.
Regulate the 💡activity of other proteins, such as enzymes and ion channels
Membrane receptors that influence the activity of cells 💡indirectly, with the transduction of an extracelular signal (ligand binding) to an intracellular one and the activation of secondary molecules.
G PROTEIN-COUPLED RECEPTORS/Metabotropic
Either 💡function as enzymes or are associated with and 💡regulate enzymes
Single pass transmembrane proteins, with extracellular and intracellular domains.
ENZYME-LINKED RECEPTORS
💡Small hydrophobic molecules that diffuse across the plasma membrane, and bind to nuclear receptors or to cytoplasmic receptors that, once bound to their ligand, translocate to the nucleus
Nuclear Receptors
Intracellular/steroid receptor
Elaborates a 💡cytosolic peptide fragment that enters the nucleus and regulates gene expression
In this signaling pathway, binding of ligand to a plasma membrane receptor leads to 💡ectodomain shedding, facilitated by members of the metalloproteinase-disintegrin family, and produces a carboxy-terminal fragment that is the substrate for 💡γ-secretase causing the 💡release of an intracellular domain of the protein that enters the nucleus and regulates transcription
Example: Sterol Regulatory Element–Binding Protein (SREBP)
Regulated Intramembrane Proteolysis (RIP)
💡Induces RIP causing the 💡release of an intracellular domain of the protein that enters the nucleus and regulates transcription
γ-Secretase
A progressive neurodegenerative brain disease characterized by the formation of 💡amyloid plaques [💡amyloid β-protein (Aβ)]
ALZHEIMER’S DISEASES
Intracellular signaling molecule
Function: Amplify, terminate thru enzymes, specific, diverse
Examples: cAMP, cGMP, Ca++, and diacylglycerol
SECOND MESSENGERS
The 💡first messenger of the signal that 💡binds to the receptor.
LIGAND
Intracellular signaling proteins that 💡relay the signal by passing the message directly to another protein
REVERSIBLE MOLECULAR SWITCHES
Cells can also adjust their sensitivity to a signal by? Whereby 💡prolonged exposure to a hormone decreases the cell’s response over time. But is a 💡reversible prcess.
DESENSITIZATION
Involves a 💡reduction in the response 💡only to the signaling molecule that caused the response.
Homologous Desensitization
Is when 💡one ligand desensitizes the response to 💡another ligand
Heterologous Desensitization
Binding of GTP (1)__, whereas hydrolysis of GTP to GDP (2)__, GTP-binding proteins.
(1) ACTIVATES
(2) INACTIVATES
Which 💡induce the hydrolysis of GTP to GDP and thus inactivate the GTPase.
GTPase-activating proteins
Causes the 💡GTPase to release 💡GDP, which is rapidly replaced by 💡GTP, thereby activating the 💡GTPase
guanine nucleotide exchange factors (GEFs)
💡Monomeric G proteins have been classified into five families that play a central role in many enzymelinked receptor pathways, and regulate gene expression and cell proliferation, differentiation, and survival:
Ras Rho Rab Ran Arf
Regulate 💡actin cytoskeletal organization, 💡cell cycle progression, and 💡gene expression.
Rho GTPases
Regulate 💡intravesicular transport and trafficking of proteins between organelles in the secretory and endocytic pathways.
Rab GTPases
Regulate 💡nucleocytoplasmic transport of RNA and proteins.
Ran GTPases
Involved in many signaling pathways that 💡control cell division, 💡proliferation and 💡death.
MUTATION = ONCOGENES
Ras GTPases
Like Rab GTPases, regulate vesicular transport
Arf GTPases
In the __, these G proteins are inactive and form a heterotrimeric complex in which GDP binds to the α subunit.
ABSENCE OF LIGAND
Ways to attenuate or terminate signaling through a GPCR:
💡💡
D
ER
- DESENSITZATION
2. ENDOCYTIC REMOVAL OF RECEPTORS
💡Inactivate the receptor and 💡promote endocytic removal of the GPCR from the plasma membrane
β-Arrestins
These are activated when a hormone binds to a GPCR which 💡phosphorylate the intracellular domain of GPCRs, which recruits proteins called 💡β-arrestins to bind to the GPCR
GPCR Kinases
It is activated when a signal molecule binds to a GPCR that interacts with a G protein composed of an 💡α subunit of the αs class.
A very common 💡downstream effector of heterotrimeric G proteins
Facilitates the conversion of 💡 ATP to cAMP
ADENYLYL CYCLASE
Secreted by 💡Vibrio cholera, catalyzes the 💡ADP ribosylation of the 💡G-protein αs subunit, which inhibits the 💡GTPase activity of αs. Thus αs remains in its activated, GTP-bound state, which in turn causes activation of 💡adenylyl cyclase and an increase in 💡cAMP/PKA levels
Elevated levels of PKA: increase 💡cystic fibrosis transmembrane conductance regulator (CFTR)–mediated 💡chloride secretion, which leads to secretory diarrhea and extensive loss of fluids, characteristic of cholera
CHOLERA TOXIN
It is secreted by 💡Bordetella pertussis, the bacterium that causes whooping cough
Which 💡ADP ribosylates the 💡αi subunit.
The ribosylation 💡inactivates αi, reducing the inhibition of 💡adenylyl cyclase and thus also leading to increased levels of 💡cAMP/PKA.
PERTUSSIS TOXIN
An 💡activated adenylyl cyclase causes an increase in cAMP levels that causes the activation of? Which regulates the 💡protein effector activity.
PROTEIN KINASE A (PKA)
When a ligand binds into this protein, it 💡inhibits the activity of adenylyl cyclase which causes the reductions in cAMP levels and consequently in PKA activity.
G protein composed of a α subunit of the αi class
cAMP is degraded to AMP by?
These are inhibited by 💡caffeine and other 💡methylxanthines making the activity of cAMP and PKA prolong.
cAMP phosphodiesterases
It is a 💡transcription factor that is activated by the 💡catalytic subunit of PKA that enter the nucleus of cells and phophorylate.
It increases the transcription of many genes, which can in turn produce a distinct set of responses with much 💡slower kinetics
cAMP response element–binding (CREB) protein
Heterotrimeric G proteins also regulate?
Phototransduction
Phospolipases
It is activated by the 💡absorption of light by 💡rhodopsin (found in the rod cells in the eye) which via the αt subunit activates ➡️cGMP phosphodiesterase.
G protein transducin
It 💡lowers the concentration of cGMP and thereby closes a cGMP-activated cation channel.
cGMP phosphodiesterase.
An 💡enzyme that converts phosphatidylinositol 4,5-biphosphate to inositol 1,4,5-triphosphate 💡 (InsP3) and 💡diacylglycerol.
PHOSPHOLIPASE C
Is a 💡second messenger that diffuses to the endoplasmic reticulum, where it activates a 💡ligand-activated Ca++ channel to release 💡Ca++ into the cytosol
InsP3
It activates 💡protein kinase C (phosphorylates effector proteins).
It releases 💡arachidonic acid via an 💡indirect pathway
DIACYLGLYCEROL
An enzyme that 💡releases arachidonic acid from 💡membrane phospholipids that is activated when a ligand binds to GPCRs.
phospholipase A2
Rising BP Weight gain Abdominal pain Water retention Elevated urine protein
PRE-ECLAMPSIA
facilitate the metabolism of 💡arachidonic acid to prostaglandins, thromboxanes, and prostacyclins
CYTOSOLIC CYCLOOXYGENASES
Mediate 💡aggregation of platelets, cause 💡constriction of the airways, and induce 💡
PROSTAGLANDIN
💡Induce platelet aggregation and 💡constrict blood vessels
It predominates in 💡PREECLAMPSIA
THROMBOXANES
💡Inhibits platelet aggregation and causes 💡dilation of blood vessels
PROSTACYCLIN
Arachidonic acid derivative involved in 💡uteroplacental blood flow.
💡💡
P
T
Prostacyclin and Thromboxane
An enzyme that initiates the conversion of arachidonic acid to 💡leukotrienes.
5-LIPOXYGENASE
An enzyme that generates 💡hydroxyeicosatetraenoic acid (HETE) and 💡cis-epoxyeicosatrienoic acid (cis-EET) from arachidonic acid.
EPOXYGENASE
-
CALMODULIN
-
CaM-dependent kinases
2 ways to terminate signal initiated by cAMP and cGMP:
- Enhancing degradation of these cyclic nucleotides by phosphodiesterases
- Dephosphorylation of effectors by protein phosphatases
4 classes of receptors that have enzymatic activity or are intimately associated with proteins that have enzymatic activity:
G
TS
T
TA
GUANYLYL CYCLASE RECEPTORS
THREONINE/SERINE KINASE REEPTORS
TYROSINE KINASE RECEPTORS
TYROSINE KINASE-ASSOCIATED RECEPTORS
It binds to the 💡extracellular domain of the plasma membrane receptor 💡guanylyl cyclase and induces a conformational change in the receptor that causes 💡receptor dimerization and activation of 💡guanylyl cyclase, which metabolizes GTP to cGMP
ATRIAL NATRIURETIC PEPTIDE (ANP)
It activates a 💡soluble receptor guanylyl cyclase that converts GTP to cGMP, which 💡relaxes smooth muscle.
NITRIC OXIDE
It 💡increases blood concentrations of nitric oxide, which increases cGMP and thereby relaxes smooth muscle in coronary arteries, it has long been used to treat 💡angina pectoris.
NITROGLYCERIN
It is a 💡threonine/serine kinase that has two subunits. Binding of TGF-β to the type II subunit induces it to 💡phosphorylate the type I subunit on specific serine and threonine residues, which in turn, 💡phosphorylates other downstream effector proteins on serine and threonine residues and thereby elicits cellular responses, 💡including cell growth, cell differentiation, and apoptosis
TGF-β receptor
Types of Tyrosine Kinase Receptors
💡💡
N
I
Nerve growth factor (NGF) receptors
Insulin receptor
have 💡no intrinsic kinase activity but 💡associate with proteins that do have tyrosine kinase activity, including tyrosine kinases of the 💡Src family and 💡Janus family.
They several 💡cytokines
TYROSINE KINASE-ASSOCIATED RECEPTORS
Arachidonic acid derivative
Allergic and inflammatory reactions causing 💡asthma, rheumatoid arthritis and inflammatory bowel disease
LEUKOTRIENES
The type of catalytic receptor that mediates 💡cellular response in the kidney 💡inhibit sodium and water reabsorption in collecting duct.
RECEPTOR GUANYLYL CYCLASE
Example of guanylyl cyclase receptors:
💡💡
A
N
Atrial natriuretic peptide (ANP) and nitric oxide
Example of threonine/serine kinase receptors:
Transforming growth factor-β (TGF-β)
Example of tyrosine kinase–associated receptors
Interleukins
Examples of effector proteins:
They are also called as heterotrimeric G proteins:
💡💡
A
PD
PL
Adenylyl cyclase, phosphodiesterases, and phospholipases (A2, C, and D)
Examples of tyrosine kinase receptors:
💡💡
EGF
P
I
EGF, platelet-derived growth factor (PDGF), and insulin
