Receptors 2

GPCRs signal through ____

heterotrimeric G proteins (alpha, beta, gamma subunits)

G-alpha-s

stimulates cAMP production

G-alpha-i

inhibits cAMP production

G-alpha-q

activates phospholipase C, increases intracellular calcium

G-alpha-12/13

promotes growth and differentiation

G protein cycle - resting state

alpha, beta, gamma subunits associated with each other and bound to GDP

inactive effector

G protein cycle - agonist binding

alpha, beta, gamma subunits associated with each other and bound to GTP. Complex bound to intracellular side of receptor.

inactive effector

G protein cycle - Effector activation

agonist bound to receptor

beta and gamma subunits associated with each other and bound to the intracellular side of the receptor

alpha subunit (bound to GTP) associated with intracellular side of effector

effector active

Pertussis toxin

secreted by the pathogen of whooping cough

locks G-alpha-i proteins in a GDP bound state

Cholera toxin

locks G-alpha-s proteins in an active state

Overproduction of cAMP → stimulate PKA in enterocytes → PKA stimulates Cl- channel activity (abnormally high Cl- in intestinal lumen) → osmosis drives water and Na+ into lumen → severe diarrhea and dehydration

Receptors coupled to G_q

M1, M3, M5

alpha 1

G_q signaling mechanisms

Activate phospholipase C to hydrolyze PIP2

increase IP₃, increase cytoplasmic Ca²⁺

increase diacylglycerol, increase PKC

Receptors coupled to G_i/G_o

M2, M4

alpha 2

G_i/G_o signaling mechanisms

decreased adenylyl cyclase

decreased cAMP

Receptors coupled to G_s

Beta 1, beta 2, beta 3

G_s signaling mechanisms

increased adenylyl cyclase

increased cAMP

What intracellular reservoir is calcium released from

endoplasmic reticulum

Regulation: desenitization

“tachyphylaxis”

diminished response of receptor to prolonged or repeated agonist exposure

Regulation: internalization

downregulation, sequestration

taken into the cell and stored in an endosome

can be recycled/reused

Regulation: degradation

first step - internalization

then taken into a lysosome and broken down

beta-arrestin

important in the process of GPCR desensitization