Pharmacodynamics: Receptors

ligand, receptor

physiological receptors: exert action by binding to a ____________, signaling/message propagation, resulting in _____________ action

second messengers

intermediary cellular signalling molecules

effector

cellular targets mediating the response

ligand-gated ion channels

receptors that directly opens an ion channel that causes hyperpolarization or depolarization

GPCR

receptors that activate signaling cascade that opens an ion channel

kinase-linked

receptors in which phosphorylation cascade that ends up changing gene transcription

nuclear receptors

ligand binds to receptor within the nucleus and affects gene transcription

ionotripic

another name for ligand-gated ion channels

metabotropic

another name for GPCRs

lipophilic

drugs that act on nuclear receptors must be _____________ to enter the cell

milliseconds

timescale for effects of ionotropic receptors

seconds

timescale for effects of metabotropic receptors

hours

timescale for effects of kinase-linked and nuclear receptors

nicotinic ACh receptor

Example of ionotropic receptor

muscarinic ACh receptor

example of metabotropic receptor

cytokine receptor

example of kinase-linked receptors

oestrogen receptor

example of nuclear receptor

ion channels

1. Ligand binds to extracellular site of the receptor

2. Conformational change of the receptor results in pore opening

3. Ion flux down electrochemical gradient

4. Pore closes

7

GPCRs have ________ transmembrane domains

dissociate

the alpha and beta/gamma subunits of a GPCR _______________ when the alpha subunit exchanges GDP to GTP after the ligand binds

RGS (regulator of G protein signaling)

protein that returns the active alpha-GTP complex to its basal state

Gs

alpha subunit:

-activates adenylyl cyclase

-activates calcium channels

Gi

alpha subunit:

-inhibits adenylyl cyclase

-activates calcium channels

Go

alpha subunit

-inhibits calcium channels

Gq

alpha subunit

-activates phospholipase C

beta-gamma

G-protein subunit that modulates ligand gated ion channels and activates the PI3 K pathway

PKA

__________ levels are increased by Gs alpha subunit when it activates AC, and decreased by Gi alpha subunit when it inhibits AC

increase, increase, decrease

Increase PKA by Gs alpha subunit (activates AC) results in:

_______________ lipolysis in liver

_______________ glycogen breakdown in liver

_______________ glycogen synthesis in liver

decrease, decrease, increase

Decrease PKA by Gi alpha subunit (inhibits AC) results in:

_______________ lipolysis in liver

_______________ glycogen breakdown in liver

_______________ glycogen synthesis in liver

calcium

cAMP activates PKA, which increases intracellular levels of _______________ and phosphorylates metabotropic enzymes

adenylyl cyclase

enzyme that converts ATP into cAMP

PLC (Phospholipase C)

enzyme that splits PIP2 into IP3 and DAG

PKC (protein kinase C)

regulates enzyme activity when activated by DAG

calcium

IP3 triggers and increase in intracellular ____________ levels, which regulates gene expression, contraction, secretion, metabolism, and electrical activity

cardiac muscle

tissue in which calcium stimulates muscle contraction

bronchial smooth muscle

tissue in which cAMP inhibits MLCK (myosin light chain kinase) which results in muscle relaxation

beta arrestin

puts phosphorylated GPCR in a coated pit ("jail") where the receptor may be resensitized or destroyed

resensitization

recovery of a receptor after agonist is removed

desensitization

destruction of receptors after continuous use of an agonist

homologous desensitization

Receptor loses ability to couple G protein and to undergo endocytosis --> desensitization initiated by activation of the receptor itself

heterologous desensitization

Phosphorylation of the activated GPCR by PKA, PKC that have been activated by another receptor --> impairing coupling of activated receptor and G protein (not specific)

tyrosine kinase

___________________ receptor:

-Ligands bind to their receptors

-Receptors dimerize, activating the tyrosine kinase

-Grb2 binds to tyrosine kinase and activates Ras, which converts GTP to GDP

-Transcription factors adjust growth

JAK-STAT

_________________ Receptor Pathway

-Cytokines bind to receptor

-Hormones (GH, prolactin)

-Promotes growth, proliferation, and cell survival (gene regulation)

GC (Guanylate Cyclase)

ANP binds to receptors coupled to _______________ enzyme and becomes active, converting GTP to cGMP

smooth muscle relaxation

cellular effect of ANP when cGMP is produced

NO

produced by endothelial cells which diffuses to adjacent cells, activating soluble GC and resulting in smooth muscle relaxation

steroid

nuclear receptors are for circulating ____________ hormones (androgens, estrogens, glucocorticoids, thyroid hormone, vitamin D)

heat shock

when steroid protein binds to its receptor, ______________ leaves and exposes the DNA binding site

downregulation

mechanism of loss of tissue receptor response in which there are reduced receptor numbers and loss of receptor binding affinity to ligands or coupling proteins

sequesterization

mechanism of loss of tissue receptor response in which receptors are internalized so they are not accessible to the ligand (failure to recycle receptor to surface)

degradation

mechanism of loss of tissue receptor response in which receptors are degraded by lysosomes