2 Neuroscience2.5 Neurochemistry and neurophysiology

2.5.2.4 Principal second messenger systems and neuronal homeostasis and plasticity

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Written by Resident Doctor Committee · Published

Second messengers

  • Second messengers are intracellular molecules that relay a signal from a first messenger bound at the cell surface.

  • The recognised examples are cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), inositol trisphosphate (IP3), diacylglycerol (DAG) and calcium.

  • G protein-coupled receptors work through second messengers, which amplify or prolong the response, whereas ligand-gated channels conduct ions directly.

G protein pathways

G protein

Effect

Receptors

Gs

Stimulates adenylyl cyclase to make cAMP, which activates protein kinase A

Beta adrenoceptors, dopamine D1/D5, serotonin 5-HT4/6/7

Gi/o

Reduces adenylyl cyclase activity

Alpha-2, D2/D3/D4, 5-HT1, muscarinic M2/M4, GABA-B

Gq

Activates phospholipase C, which splits a membrane phospholipid into IP3 and DAG

Alpha-1, 5-HT2, M1/M3/M5, group I metabotropic glutamate

  • IP3 releases calcium from endoplasmic reticulum stores, and membrane-bound DAG works with calcium to activate protein kinase C.

Follow each column down from receptor to kinase: Gs raises cyclic AMP to activate protein kinase A, Gi/o lowers cyclic AMP, and Gq activates phospholipase C, whose products IP3 and DAG raise calcium and activate protein kinase C. Drawn for MRCPsychiatrist

Calcium and plasticity

  • Resting cytoplasmic calcium is about 100 nM, and pumps, exchangers, stores and binding proteins hold it far below extracellular levels.

  • Calcium bound to calmodulin activates calcium/calmodulin-dependent protein kinase II (CaMKII) and calcineurin.

  • A brief, large calcium rise favours CaMKII and potentiation, while a smaller, sustained rise favours calcineurin and depression.

  • Brain-derived neurotrophic factor acts on receptor tyrosine kinases and drives gene transcription that supports survival and plasticity.

  • Short-term change uses phosphorylation and trafficking, but lasting potentiation needs transcription and protein synthesis.

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