cyclic AMP signalling

G protein-coupled receptors (GPCRs)

Cell surface receptors involved in vision, smell, taste, mood, cognition, and autonomic control such as heart rate and digestion

GPCR structure

Receptors with seven transmembrane alpha-helices that span the membrane seven times

Heterotrimeric G protein

A guanine nucleotide–binding protein composed of alpha, beta, and gamma subunits

G protein alpha subunit

Binds GDP in the inactive state and GTP in the active state

G protein beta and gamma subunits

Remain associated as a complex and interact with effectors after activation

GPCR activation

Ligand binding causes a conformational change in the receptor’s intracellular region

GPCR as a GEF

Activated GPCR acts as a guanine nucleotide exchange factor that promotes GDP release from the G protein

GDP to GTP exchange

GTP binds to the alpha subunit due to higher intracellular GTP concentration

Activated G protein

GTP-bound alpha subunit dissociates from beta-gamma and interacts with effectors

Molecular basis of G protein activation

The terminal phosphate of GTP stabilizes switch I and switch II regions via hydrogen bonds

G protein off mechanism

Alpha subunit hydrolyses GTP to GDP, returning the protein to its inactive state

GTPase activity of G proteins

Intrinsic hydrolysis of GTP is slow without regulatory proteins

GTPase-activating proteins (GAPs)

Proteins that accelerate GTP hydrolysis on G proteins

Regulators of G protein signalling (RGS)

GAPs specific for heterotrimeric G proteins

Gs protein signalling

Activated Gs stimulates adenylyl cyclase to produce cyclic AMP

Adenylyl cyclase

Enzyme that converts ATP into cyclic AMP

Cyclic AMP (cAMP)

A second messenger that activates downstream signalling pathways

Phosphodiesterases

Enzymes that degrade cyclic AMP to limit signal spread

Protein kinase A (PKA)

A serine/threonine kinase activated by cyclic AMP

Inactive PKA

Consists of two regulatory subunits bound to two catalytic subunits

PKA activation

Binding of cyclic AMP causes regulatory subunits to release catalytic subunits

PKA regulatory subunit function

Blocks the active site of the catalytic subunit when cAMP is absent

Scaffold proteins

Proteins that organise signalling components to increase specificity

A-kinase anchoring proteins (AKAPs)

Scaffold proteins that anchor PKA near its targets

AKAP function

Ensures rapid and specific phosphorylation by activated PKA

AKAP signalling complexes

Often include phosphodiesterases and phosphatases for signal termination

Cardiac muscle contraction trigger

Calcium entry through voltage-gated Ca2+ channels

Calcium-induced calcium release

Entry of Ca2+ triggers further release from intracellular stores

Adrenaline effect on heart

Activates GPCRs that increase cyclic AMP and PKA activity

PKA effect on Ca2+ channels

Phosphorylation increases calcium entry into cardiac cells

PKA effect on Ca2+ release channels

Increases sensitivity of calcium stores to trigger Ca2+

Termination of contraction signal

Calcium is pumped back into stores or out of the cell