Drug Receptors — Ion Channel, GPCR, Enzyme-Linked and Nuclear Receptors

A receptor is a specific protein that binds a signalling molecule (a neurotransmitter, hormone, growth factor or a drug) and converts that binding into a cellular response. Drugs mostly work by imitating or blocking a natural ligand at its receptor. Most signal molecules are hydrophilic and cannot cross the plasma membrane, so they act on cell-surface receptors; small hydrophobic molecules such as steroid hormones cross the membrane and act on intracellular receptors.

Cell-surface receptors belong to three classes defined by their transduction mechanism: ion-channel-linked, G-protein-linked and enzyme-linked receptors. Add the intracellular (nuclear) receptors and you have the standard four-family classification used in pharmacology.

Ion-channel-linked receptors, also called transmitter-gated ion channels, mediate rapid synaptic signalling between excitable cells. A small number of neurotransmitters briefly open or close the channel formed by the very protein they bind to, changing the ion permeability of the membrane and the excitability of the postsynaptic cell. Receptor and effector are one protein, so there is no second messenger.

• Nicotinic acetylcholine receptors are ionotropic (ligand-gated) and work at the neuromuscular junction and in the CNS, in contrast to muscarinic receptors, which are GPCRs.
• GABA-A and glycine receptors are ligand-gated chloride channels and mediate inhibitory synaptic signalling in the CNS. Both are pentameric transmembrane proteins.
• The GABA-A receptor has binding sites for benzodiazepines, barbiturates, zolpidem/zaleplon and flumazenil; the glycine receptor has a binding site for strychnine.

GPCRs are integral membrane proteins with an extracellular N-terminus, seven transmembrane α-helices and an intracellular C-terminus. They are the largest family of membrane receptors: the human genome encodes nearly 800 of them, about 90% in the rhodopsin family, and GPCRs account for roughly 30% of all identified drug targets.

1. The ligand binds and changes the receptor's shape.
2. The receptor acts as a guanine nucleotide exchange factor: the Gα subunit releases GDP and binds GTP, and the G protein activates.
3. The activated G protein switches an effector (enzyme or ion channel) on or off.
4. Gα has GTPase activity; hydrolysing GTP to GDP switches the signal off (RGS proteins speed this up).

Enzyme-linked receptors have an extracellular ligand-binding region, a single transmembrane helix and a cytoplasmic region that either has intrinsic enzyme activity or associates with an enzyme. The best-known group is the receptor tyrosine kinases (RTKs): 58 known human RTKs in 20 subfamilies, which regulate cell differentiation, proliferation, survival, metabolism and migration. Most bind a soluble growth-factor peptide.

• The intracellular tyrosine kinase domain phosphorylates tyrosine residues; adaptor proteins (for example Grb2) bind these phosphotyrosines through SH2 domains.
• Main downstream routes: MAPK/ERK, PI3K/Akt/mTOR and PLCγ/PKC, which drive gene transcription for proliferation and survival.
• Insulin and IGF-1 receptors are RTKs: insulin receptor binding stimulates glucose uptake, glycogenesis and lipogenesis.
• EGFR/HER2 overexpression drives some cancers. Drugs are either monoclonal antibodies (trastuzumab and pertuzumab block HER2 dimerisation) or small-molecule tyrosine kinase inhibitors that stop kinase phosphorylation.

Guanylyl cyclase receptors are a second enzyme-linked type. The membrane form has intrinsic guanylyl cyclase activity and is activated by atrial natriuretic peptide (ANP) and BNP; the soluble form in the cytoplasm is activated by nitric oxide (binding a haem group). Both convert GTP to cGMP, which activates protein kinase G and causes smooth-muscle vasodilation.

A number of small hydrophobic signal molecules diffuse straight across the plasma membrane and bind intracellular receptor proteins that act as ligand-activated gene regulatory proteins. The ligands include steroid hormones, thyroid hormones, retinoids and vitamin D. Despite very different structures, they all act by a similar mechanism: the ligand-bound receptor binds DNA and changes gene transcription.

Because a response needs new gene expression and protein synthesis, it usually takes hours to appear, which is why steroid and thyroid hormone effects are slow in onset. See corticosteroids and hormone mechanisms.

Traditional theory held that receptors were silent until a ligand arrived. We now know receptors can be active without a ligand (constitutive activity), which is why inverse agonists exist. An agonist may give a maximal response without occupying all receptors — the old idea of 'spare receptors' or receptor reserve; the review cautions that all receptors still participate, but not all are needed for the maximum response.

• GPCR mutations cause retinitis pigmentosa (rhodopsin) and have been linked to hypothyroidism, hyperthyroidism, nephrogenic diabetes insipidus and fertility problems.
• G-protein toxins: cholera (Gαs locked active) and pertussis (Gαi inactivated).
• RTK overexpression: HER2-positive breast cancer, treated with trastuzumab and pertuzumab.
• Ligand-gated chloride channels: benzodiazepine and barbiturate sites on GABA-A; strychnine blocks the glycine receptor.
• Guanylyl cyclase pathway: natriuretic peptides and nitric oxide drive cGMP-mediated vasodilation.

For receptor-specific examples see adrenergic drugs and receptors, autacoids and anticancer drug mechanisms.

• Classify the receptor: nicotinic (ion channel), muscarinic (GPCR), insulin (tyrosine kinase), steroid (nuclear), ANP (guanylyl cyclase).
• Fastest to slowest response among receptor types.
• Second messenger: Gs → cAMP ↑; Gi → cAMP ↓; Gq → IP₃/DAG.
• Toxin and G protein: cholera → Gs; pertussis → Gi.
• Definitions: partial agonist, inverse agonist, competitive antagonist.