Receptors

Receptors are proteins that are targets for drug action and are located in the membrane or intracellularly. Many receptor classes have subtypes with different locations and physiological roles. For example, noradrenaline acts at:

• α₁-adrenoceptors (e.g. vascular smooth muscle)
  
• α₂-adrenoceptors (e.g. CNS, presynaptically)
  
• β₁-adrenoceptors (e.g. heart)
  
• β₂-adrenoceptors (e.g. airways).

Acetylcholine acts at nicotinic (N) receptor subtypes at autonomic ganglia and neuromuscular junctions, and in the parasympathetic nervous system at muscarinic (M) receptors.

7-transmembrane receptors: many receptors are transmembraneous and are coupled to G-proteins (G-protein-coupled receptors, GPCR). For example, β-adrenoceptors following activation are coupled via a G-protein, which leads to activation of adenylyl cyclase, and the formation of cAMP, which leads to a pharmacological response. These receptors are referred to as metabotropic (Figure 7.1).

G-proteins: heterotrimeric proteins (α, β and γ subunits), and at rest the α subunits bind GDP, but following coupling to an activated receptor a conformation change results in exchange of GDP for GTP and the α-GTP subunit dissociates. This leads to the α-GTP subunit interacting with coupled enzymes such as adenylyl cyclase and phospholipases (releasing membrane-derived second messengers) or ion channels. There are many subtypes and they can be stimulatory or inhibitory. They undergo a cycle such that activated α-GTP has intrinsic GTPase activity, and when α-GDP is formed the subunit can reassociate with the β and γ subunits (Figure 7.2).

Intracellular or nuclear receptors: located within the cell and are activated by lipophilic molecules such as steroids, which pass through the membrane and enter the cytoplasm. Once the receptor is activated the resulting complex influences DNA transcription, resulting in the production or suppression of mRNA and target proteins, and so their effects are delayed.

Receptors coupled to enzymic activity (catalytic receptors): activation of these receptors results in activation of enzymic activity. For example, an insulin receptor has intrinsic tyrosine kinase activity, such that activation leads to autophosphorylation of tyrosine residues on the receptor, which is coupled to the cellular responses.

Receptors linked to ion channels (ligand-gated ion channels): these are ionotropic receptors and activation leads to altered channel function. For example, at neuromuscular junctions (NMJs) acetylcholine activates N receptors and this leads to channel opening (Chapter 22). This is part of the receptor complex and results in ion (predominantly Na⁺) influx and depolarisation of the skeletal muscle, which ultimately leads to contraction (Figure 7.3).

Responses linked to ionotropic receptors can be inhibitory. For example, in the central nervous system (CNS) the inhibitory neurotransmitter gamma-amino butyric acid (GABA) acts at the GABA_A receptor and causes activation of its chloride channel. This results in the influx of Cl⁻ and hyperpolarisation, which reduces cell excitability. Benzodiazepines (e.g. diazepam) modulate the GABA_A receptor and augment the actions of GABA.