Cell signalling and receptors

Signals act over different distances: endocrine (hormones in blood), paracrine (local diffusion), autocrine (on the secreting cell itself), synaptic (neurotransmitters) and contact-dependent/juxtacrine (e.g. Notch–Delta). Hydrophilic signals bind cell-surface receptors; small lipophilic signals (steroid and thyroid hormones, vitamin D, retinoic acid) cross the membrane and bind intracellular (nuclear) receptors, zinc-finger transcription factors that bind hormone-response elements in DNA — a slow but long-lasting response.

There are three main classes of surface receptor. Ion-channel-linked receptors (nicotinic ACh, GABA-A, glutamate receptors) open in milliseconds. G-protein-coupled receptors (the largest family, with seven transmembrane helices) activate heterotrimeric G proteins by exchanging GDP for GTP on the α subunit: Gs stimulates adenylyl cyclase → cAMP → protein kinase A; Gi inhibits adenylyl cyclase (its βγ subunits also open K⁺ channels); Gq activates phospholipase C-β, which cleaves PIP₂ into IP₃ (releases Ca²⁺ from the ER) and DAG (activates protein kinase C). The signal ends when Gα hydrolyses its GTP. Enzyme-linked receptors include receptor tyrosine kinases (insulin, EGF, PDGF, VEGF receptors) that dimerise, autophosphorylate and recruit adaptor proteins to activate the Ras–MAPK and PI3K–Akt pathways; cytokine receptors that use associated JAK kinases to phosphorylate STAT transcription factors; serine/threonine-kinase receptors for TGF-β that act via SMADs; and the natriuretic-peptide receptors with intrinsic guanylyl cyclase (→ cGMP). Nitric oxide, a gas, activates soluble guanylyl cyclase directly.

Cascades amplify signals enormously (one receptor can generate thousands of second-messenger molecules), integrate multiple inputs, and are switched off by phosphatases, phosphodiesterases (cAMP/cGMP breakdown), receptor desensitisation (phosphorylation by GRKs, β-arrestin) and endocytosis.