There are four classes of drug receptors, G protein-coupled receptors, ligand-gated ion channels, enzyme-linked receptors (receptor tyrosine kinases and cytokine receptors), and intracellular nuclear receptors, each of which transmits its signals through different, but well-defined pathways, from ligand binding to cellular action. ⓘ Quick overview Most receptor pharmacology is organized into four classes: ligand-gated ion channels, GPCRs, tyrosine kinase-coupled/enzyme-linked receptors and intracellular nuclear receptors, which is the organization that is widely used in clinical pharmacology and anesthesiology education. In practice, these classes are distinguished by location (membrane vs intracellular), coupling (ions, G proteins, kinases, transcription), and kinetics (milliseconds to hours), which have a direct correlation to therapeutic onset and duration of action. ⚡ Ligand-gated ion channels Ligand-gated ion channels (LGICs, ionotropic receptors) are transmembrane proteins that, when bound by an orthosteric ligand, open a selective pore to ions like Na+, K+, Ca2+ or Cl- and thus convert during milliseconds, the chemical signals of neurotransmitters to the swift electrical responses. Typical LGICs are the nicotinic acetylcholine receptor and the GABA_A receptor. LGICs mediate fast synaptic transmission at distal synapses and central junctions; gating and allostery allow phasic or tonic signaling, depending on the receptor localization and local transmitter concentration. Some channel proteins support ion selectivity (depolarization - excitatory or hyperpolarization - inhibitory) and many LGICs also comprise allosteric receptors for modulators or blockers, providing an understanding of the mode of action of drugs such as benzodiazepine potentiation via the GABA_A receptor and the NMDA channel block by ketamine. ⚙️ Mechanistic steps Orthosteric interaction of the ligand at the extracellular domain causes a conformational change and propagates to the transmembrane domain resulting in pore gating, a phenomenon called gating isomerization which structurally separates binding of the ligand with the channel opening. Allosteric ligands and endogenous modulators can exist across the gating equilibria, modulate open probability, and/or desensitization, thereby explaining pharmacological profiles and therapeutic windows in different therapeutic agents of the channel target sites. 🩺 Clinical implications Because action of LGICs is within milliseconds, drugs acting at LGICs have rapid onset (e.g. neuromuscular blockers at nicotinic receptors; anaesthetics at GABA_A/NMDA), and antagonists act either as competititors at the orthosteric site or as noncompetitors blocking the channel pores (portioned reversal strategies, safety profiling). Response modifiers such as a decrease in responsiveness to prolonged treatment due to the desensitization of receptors and variation in subunit composition across various tissues affect pharmacologic sensitivity and adverse effect profiles. 🛠️ G protein coupled receptors (GPCRs) GPCRs are seven transmembrane receptors and also guanine nucleotide exchange factors for heterotrimeric G proteins, and GPCR stimulation leads to stabilization of an active conformation, which then catalyzes the exchange of GDP and GTP on Ga, resulting in Ga-Gbg dissociation and activation of downstream effectors and second messengers. The four canonical Gα classes—Gs, Gi/o, Gq/11, and G12/13—link GPCRs to cAMP/PKA, inhibition of adenylyl cyclase, PLCβ→IP3/DAG/Ca²⁺/PKC, and Rho GTPase signaling, respectively, producing diverse cellular outcomes from metabolism to contractility. GPCR signaling has bimodal aspects: G protein-domain dependent signaling is performed in parallel with β-arrestin dependent signaling that occur to mediate desensitization, endocytosis and unique interactions to kinase signaling (e.g., ERK scaffolding) such that "biased" signaling profiles are thus possible on a ligand by ligand basis. 🛡️ Desensitization and β‑arrestins Upon repeated or sustained agonism, GPCR kinases (GRKs) phosphorylate active receptors, promoting β‑arrestin binding that sterically prevents further G protein coupling and scaffolds enzymes (e.g., PDE4, DGKs) to dampen second messengers, a core mechanism of acute desensitization. β‑arrestins also assemble signaling complexes (e.g., ERK, JNK, Src) at the plasma membrane or endosomes, producing sustained, spatially restricted signals distinct from transient nuclear ERK waves driven by G proteins, which underlies functional selectivity of GPCR responses. ⚖️ Biased agonism Ligands can selectively stabilize receptor conformations that preference to the G protein vs b-arrestin pathways (or vice versa), creating therapeutic opportunity to increase desired clinical effects while mitigating adverse events as exemplified by novel GPCR-targeting analgesics and cardiometabolic agents currently in development. GRK isoform-selective phosphorylation of C-tails encodes b-arrestin conformations and functions and the selectivity of GRK isoform-mediated bias and trafficking depends on cell type, receptor C-tail sequence, and ligand chemistry. 🗂️ Enzyme linked receptors: RTKs & cytokine receptors Enzyme‑linked receptors include receptor tyrosine kinases (RTKs) with intrinsic kinase domains and cytokine receptors that signal via non‑receptor tyrosine kinases such as JAKs, both converting extracellular growth factor or cytokine binding into phosphorylation cascades and transcriptional reprogramming. RTKs (e.g., EGFR, VEGFR, PDGFR) are activated when ligand binding stabilizes receptor dimerization or oligomerization, enabling trans‑autophosphorylation on specific tyrosines that both activate the kinase and create SH2/PTB docking sites for adaptor proteins and enzymes. The phosphorylated tail recruits effectors to Ras–MAPK, PI3K–Akt, and PLC‑γ pathways, coordinating proliferation, differentiation, survival, angiogenesis, and motility, while the precise tyrosine motif context confers pathway specificity. 📝 RTK mechanism step-by-step Ligand binding exposes or stabilizes a dimerization interface, RTK protomers pair, and their kinase domains trans‑autophosphorylate activation loops and C‑terminal tails, switching on catalytic activity and building high‑affinity docking sites for SH2/PTB domain proteins such as Grb2, Shc, PI3K, and PLC‑γ. Adaptor engagement triggers cascades: Grb2–SOS activates Ras→Raf→MEK→ERK (MAPK), PI3K generates PIP3 to recruit PDK1/Akt (survival/growth), and PLC‑γ hydrolyzes PIP2 to IP3/DAG to mobilize Ca²⁺ and activate PKC, integrating signals by context to yield distinct cellular outcomes. 🦠 Cytokine receptors and STAT Cytokine receptors have no kinase activity, but constitutively bind to Janus kinases (JAKs); cytokine binding causes receptor juxtaposition that leads to the trans-activation of JAKs, which, in turn, phosphorylate receptor tails, leading to the recruitment of the transcription factors of the signal-dependent transcription factor family (STATs), as well as their phosphorylation, dimerization, and nuclear translocation. JAK-STAT signaling is parsimonious - receptor, kinase and transcription factor - but powerful, directing the development, proliferation, and effector functions of immune cells with negative feedback controls to ensure the termination of a signal at the right time. ⚛️ Intracellular (nuclear) receptors Slower onsets, and durable genomic effects, may be explained by slower effects of nuclear receptors, which are nuclear transcription factors which bind a variety of lipid…
