Chapter 19 - Signal Transduction

antigens, hormones, neurotransmitters, light, touch, and pheromones

6 types of signals that cells can received from the environment

receptor

membrane-bound or soluble protein or protein complex, which exerts a physiological effect after binding its natural ligand

• G-protein coupled receptors (epinephrine receptor)

• Enzyme-linked receptors (insulin receptor)

• Other membrane receptors (integrin receptor)

• Nuclear receptors (steroid receptor)

4 types of receptors and an example of it

• specificity

• amplification

• modularity

• desensitization/adaptation

• integration

5 features of signal-transducing systems

signal molecule fits binding site on its complementary receptor; other signals do not fit

explain specificity feature of signal-transducing systems

when enzymes activate enzymes, the number of affected molecules increases geometrically in an enzyme cascade

explain amplification feature of signal-transducing systems

proteins with multivalent affinities form diverse signaling complexes from interchangeable parts

explain modularity feature of signal-transducing systems

receptor activation triggers a feedback circuit that shuts off the receptor

explain desensitization/adaptation feature of signal-transducing systems

when 2 signals have opposite effects on a metabolic characteristic, the regulatory outcome is the integrated input from both

explain integration feature of signal-transducing systems

1. small ions (ferric ion)

2. organic molecules (adrenalin)

3. polysaccharides (heparin)

4. peptides (insulin)

5. proteins (vascular endothelial growth factor)

what are the 5 typical ligands and an example of each

measure total binding, measure nonspecific binding in the absence of receptors, and subtract NSB from the total to get specific binding

how to calculate specific binding from nonspecific binding

external ligand binds to receptor which activates an intracellular GTP-binding protein which regulates an enzyme that generates an intracellular second messenger

explain G protein-coupled receptor

ligand binding activates tyrosine kinase activity by autophosphorylation which leads to kinase cascade which activates transcription factor in nucleus, altering gene expression

explain receptor tyrosine kinase

ligand binding to extracellular domain stimulates formation of a second messenger cGMP

explain receptor guanylyl cyclase

channel opens or closes in response to concentration of signal ligand or membrane potential which either allows ion to flow through or not

explain gated ion channel

binds molecules in extracellular matrix, changes conformation, thus altering its interaction with cytoskeleton

explain adhesion receptor (integrin)

hormone binding allows the receptor to regulate the expression of specific genes

explain nuclear receptor

adenylate cyclase

which enzyme would produce cAMP

they are α-helical integral membrane proteins

what type of proteins are G-protein coupled receptors (GPCRs)

heterotrimeric (αβγ) membrane-associated proteins

what type of proteins are the G-proteins

they mediate signal transduction from G-protein coupled receptors to other target proteins

what is the role of G-proteins

μ-opioid receptor

GPCR that is the target of morphine and codeine

β₂-adrenergic receptor

GPCR that is the target for catecholamines like epinephrine

made in the adrenal glands which are a pair or organs on top of kidneys

what glands is the hormone epinephrine made in (and where are these glands located)

breakdown of glycogen

what does binding of epinephrine to receptors in muscle or liver cell induce

lipid hydrolysis

what does binding of epinephrine to receptors in adipose cells induce

increases heart rate

what does binding of epinephrine in heart cells do

its affinity for its receptor → the lower the number the less is dissociates meaning the affinity is greater

what does the dissociation constant tell us about the ligand

it’s an agonist of epinephrine and used for treatment of bradycardia (slow heart rate) and heart block

what is isoproterenol and what is it used for

it’s an antagonist of epinephrine and used as a beta-blocker to slow heart rate

what is propranolol and what is it used for

agonist

substance that initiates a physiological response when combined with a receptor

antagonist

chemical that acts within the body to reduce the physiological activity of another chemical substance

makes breathing easier by relaxing muscles in the airways

how does EpiPen work

1. epinephrine binds to its receptor (β-adrenergic receptor)

2. causes the GDP bound to G_sa to be replaced by GTP, activating it

3. the activated G-protein separates from complex and activates adenylyl cyclase

4. adenylyl cyclase catalyzes the formation of cAMP

5. cAMP activates PKA

6. PKA can phosphorylate cellular proteins to cause cellular response

how does epinephrine trigger response vis G-protein coupled receptor

produce glucose from glycogen

PKA activation leads to activation of enzymes that produce what from what

• activation of a few GPCRs leads to activation of a few adenylyl cyclase enzymes

• every active adenyl cyclase enzyme makes several cAMP molecules which activate several PKA enzymes

• these activate thousands of glycogen-degrading enzymes resulting in tens of thousands of glucose molecules

explain signal amplification in epinephrine cascade

self-inactivation of G-protein → hydrolysis of GTP in the α subunit of the G-protein

how is cAMP down regulated to stop glucose synthesis once there is no need to “fight or flee”

1. binding of epinephrine to β-adrenergic receptor triggers dissociation of G_sBy from G_sa

2. G_sBy recruits βARK to the membrane where it phosphorylates Ser residue at the carboxyl terminus of the receptor

3. βarr binds to the phosphorylated terminal domain of the receptor

4. complex enters the cell by endocytosis

5. in endocytic vesicle, arrestin dissociates and the receptor is dephosphorylated and returned to cell surface

steps of desensitization of β-adrenergic receptors

localization of protein kinase A → PKA is localized to particular structures by anchoring proteins and different anchors are expressed in different cell types to determine the downstream effect of cAMP

how is cAMP able to mediate multiple signals

cholera toxin and pertussis toxin

what toxins function as enzymes that inactivate G-proteins and cause adenylate cyclase to be constitutively active and produce too much cAMP

IP₃ and/or Ca²⁺

what else can GPCRs use as secondary molecules

calmodulin

calcium is able to modulate the function of many enzymes through what mediator

calmodulin

calcium-binding messenger protein expressed in all eukaryotic cells