3 Clinical psychopharmacology3.3 Pharmacodynamics

3.3.1.6 Intracellular effects of receptor activation

3 min read2 figures

Written by Resident Doctor Committee · Published

From binding to response

Receptor

Mechanism

Ionotropic

Gates its own channel directly and rapidly

Metabotropic

Acts through intracellular steps that amplify and prolong signalling

Compare the two panels: the ionotropic AMPA receptor gates its own sodium channel within about a millisecond, while the metabotropic D1 receptor works through Gs, adenylyl cyclase, cAMP and protein kinase A over hundreds of milliseconds to seconds. Drawn for MRCPsychiatrist

  • Amplification happens because one receptor activates many G proteins, each generating many second messengers.

The cyclic AMP pathway

G protein

Effect

Receptors

Gs

Stimulates adenylyl cyclase, raising cyclic adenosine monophosphate (cAMP)

Dopamine D1 and D5, beta-adrenergic, serotonin (5-HT) 4, 6 and 7

Gi/o

Inhibits some cyclase isoforms, lowering cAMP

D2-like, alpha-2, 5-HT1, opioid, cannabinoid CB1, gamma-aminobutyric acid B (GABA-B)

  • Protein kinase A is released by cAMP and phosphorylates channels, enzymes, receptors and transcription factors.

  • CREB (cAMP response element-binding protein), once phosphorylated, switches on plasticity and survival genes, including brain-derived neurotrophic factor.

  • Phosphodiesterases break down cyclic nucleotides: sildenafil inhibits phosphodiesterase 5, which is cyclic GMP-specific, and caffeine inhibits phosphodiesterases at high concentrations.

The phospholipase C pathway

  • Gq activates phospholipase C beta, which cleaves phosphatidylinositol bisphosphate (PIP2) into inositol trisphosphate and diacylglycerol.

  • Inositol trisphosphate releases calcium from the endoplasmic reticulum, and diacylglycerol with calcium activates protein kinase C.

  • Gq-coupled receptors include alpha-1, 5-HT2, muscarinic M1, M3 and M5, and group I metabotropic glutamate receptors.

  • Lithium inhibits inositol monophosphatase, depleting inositol for PIP2 most in highly active cells; glycogen synthase kinase 3 (GSK-3) inhibition is another proposed mechanism.

Follow each column down from the receptor: Gs raises cyclic AMP and activates protein kinase A, Gi/o lowers cyclic AMP, and Gq activates phospholipase C, which splits PIP2 into IP3 for calcium release and DAG for protein kinase C. Drawn for MRCPsychiatrist

Calcium and cyclic GMP

Calcium enters through voltage-gated and ligand-gated channels or leaves intracellular stores, then binds calmodulin and activates calcium/calmodulin-dependent kinase II (CaMKII).

Calcium signal

Outcome

Brief microdomain at the presynaptic active zone

Vesicle fusion within microseconds

Large, brief postsynaptic rise through N-methyl-D-aspartate receptors

CaMKII activation and long-term potentiation

Small, sustained rise

Phosphatases favoured, giving long-term depression

Large, sustained rise

Proteases and nitric oxide synthase activated, killing the cell

  • Excitotoxicity follows when buffers, pumps, mitochondria and endoplasmic reticulum fail to control calcium.

  • Cyclic GMP (guanosine monophosphate) comes from soluble guanylyl cyclase, which nitric oxide activates, or from natriuretic peptide receptors, and activates protein kinase G.

  • Nitric oxide can diffuse across synapses as a retrograde signal.

Kinase networks

Network

Function

Mitogen-activated protein kinase

Links receptor and growth factor signals to transcription

Phosphoinositide 3-kinase and Akt

Control metabolism and survival, with GSK-3 downstream

Mechanistic target of rapamycin (mTOR)

Couples growth and energy signals to local protein synthesis; the proposed route for ketamine's rapid antidepressant effect

Channels and synaptic strength

  • G beta-gamma subunits open potassium channels and inhibit presynaptic calcium channels, contributing to opioid, cannabinoid, GABA-B and alpha-2 effects.

  • AMPA receptor insertion or removal changes synaptic strength, and lasting plasticity also needs protein synthesis.

  • c-Fos and Arc are immediate early gene products used experimentally as markers of neuronal activity.

Adaptation, tolerance and withdrawal

Clinical effect

Timing

Sedation, postural hypotension, acute dystonia

Often early, from direct receptor effects

Antidepressant and antipsychotic effects

Develop over weeks alongside cellular adaptation

  • Desensitisation occurs when kinases and beta-arrestin reduce G protein coupling and promote receptor internalisation; recycling restores receptors and degradation reduces their number.

  • Sustained agonism often downregulates receptors, while antagonism can upregulate them and cause rebound after withdrawal.

  • Tolerance can involve altered phosphorylation, coupling, receptor availability and opposing transmitter systems.

  • Withdrawal occurs when drug removal outpaces reversal of these adaptations.

Revision material for the MRCPsych examinations. Not clinical guidance, and not for use in patient care.