Drug Receptor Types & Signal Transduction

• Physiological receptors mediate ligand binding via a ligand-binding domain and propagate messages via an effector domain.
• Drugs modify cellular function by binding to receptors, initiating, enhancing, diminishing, or terminating signals.

Signal Transduction Pathway

• This pathway, also known as the receptor-effector coupling mechanism, encompasses the receptor, its cellular target, and intermediary molecules.

Major Types of Drug Receptors

• Include ion channels, G protein-coupled receptors (GPCRs), transmembrane receptors with enzymatic cytosolic domains, and intracellular receptors.

Ion Channels

• Membrane lipid bilayers are largely impermeable to polar ions, requiring them to be non-polar and lipophilic to pass through.
• These channels play vital roles in neurotransmission, cardiac conduction, muscle contractions, and secretion.
• Classified by architecture, ions conducted, and activation mechanism, with ligand and voltage-activated channels being major drug targets.

Ligand-Activated Ion Channels

• They are diverse, with major types found in the CNS, responding to excitatory neurotransmitters like acetylcholine (ACh) or glutamate, and inhibitory neurotransmitters like glycine or GABA.
• The nicotinic acetylcholine receptor, found in skeletal muscle and neurons consists of 5 subunits (2-α, β, γ, δ) in skeletal muscle. Activation requires two ACh molecules binding to α subunits.
• Activation results in a conformational change, pore opening, and Na+ passage and K+ passage.

Voltage-Activated Ion Channels

• Examples include Na+, K+, Ca2+, and Cl- channels.
• Voltage-activated Na+ channels initiate action potentials, depolarizing the membrane from -70mV to +30mV, then becoming inactivated until reset.
• Drugs can exhibit state-dependent affinity, such as local anesthetics like lidocaine which prolong the refractory period.

Other Ion Channels

• These are activated by intracellular molecules, such as the sulfonylurea receptor (SUR1), which regulates the ATP-dependent K+ channel in pancreatic beta-cells.
• Sulfonylurea class oral hypoglycemics like Glipizide facilitate channel closure and insulin secretion by binding to SUR1.

G Proteins

• G protein-coupled receptors (GPCRs) are the most abundant class of receptors in the body, with humans expressing over 800 types dedicated to sensory perception and regulating various physiological functions.
• GPCRs can be activated by neurotransmitters, eicosanoids, peptide hormones, and opioids and are the targets of many drugs.
• GPCRs bind to heterotrimeric GTP-binding regulatory proteins termed G proteins.
• Signals from G proteins are usually terminated by hydrolysis of GTP to GDP by inherent GTP-ase activity of the alpha subunit.
• G proteins activate effector molecules, producing second messengers like adenylyl cyclase, guanylyl cyclase, phospholipase C, and various ion channels.
• While G alpha subunit isoforms are well-known, βγ subunit isoforms can regulate K+ and Ca2+ channels.

β-Adrenergic Receptor Group

• This is an important receptor class in the G protein receptor family.
• Catecholamines (epinephrine and norepinephrine) are endogenous ligands, stimulating cAMP production and tissue-specific cellular effects.

Transmembrane Receptors

• These receptors have enzymatic cytosolic domains and play essential roles in cell metabolism, growth, and differentiation; tonic activation can cause tumors.
• Unlike GPCRs, they consist of single membrane-spanning proteins and often form dimers or multi-subunit complexes for signal transduction.
• Receptor activity includes adding/removing phosphate groups from specific amino acids like phosphorylation.

Receptor Tyrosine Kinases

• It is the largest group of this receptor class.
• Endogenous ligands include insulin, PDGF, and VEGF. Effectors include SH2 domains on signaling molecules like Grb2.
• Imatinib (Gleevec) is a TK inhibitor used as an anticancer agent targeting BCR-Abl TK in chronic myelogenous leukaemia.

Tyrosine Kinase-Associated Receptors

• Includes cytokine receptors like γ-interferon and growth hormone and prolactin receptors.
• These receptors lack intrinsic enzymatic activity; dimerization allows binding of intracellular tyrosine kinases like Janus Kinase (JAK).
• JAKs phosphorylate other proteins (STAT), which translocate to the nucleus.

Intracellular Receptors

• Nuclear hormone receptors: circulating steroid hormones are lipophilic, diffusing through the plasma membrane to bind transcription factors.
• Receptors possess a ligand-binding domain and a DNA-binding domain.
• Nuclear events depend on co-activators or co-repressors of gene transcription.
• Gene transcription is slow but has long-lasting effects, exhibiting a lag on (slow onset) and lag off (slow offset).

Nitric Oxide (NO)

• It is a labile gas produced locally, especially in the cardiovascular system via endothelial (eNOS), inductible (iNOS), and neuronal (nNOS) isoforms.
• NO binds to the N-terminal domain of soluble guanylyl cyclase (GC), enhancing cGMP activation.

Vascular Smooth Muscle Effects of cGMP

• Mainly due to cGMP acting on PKG, leading to vasodilation from reduced intracellular calcium levels. e.g., nitrovasodilators and angina pectoris.

Other Drug Receptors

• Some drug receptors exist outside the plasma membrane with roles such as communication: ACE inhibitors (enalapril) for hypertension.
• Neurotransmitter: acetylcholinesterase inhibitors (tacrine) for Alzheimer's disease.
• Cell surface adhesion function: Eptifibatide, an antagonist of the platelet GPIIb-IIIa receptor, inhibits platelet aggregation.
• Structure: Microtubule inhibitors (paclitaxel) for cancer therapy.

Cellular Signal Integration

• Signaling convergence by second messengers can generate coordinated net cellular effects.

Signal Amplification

• The magnitude of a cellular response to a ligand is generally greater than the initiating stimulus.

Cellular Regulation of Receptors

• Drug-induced activation or inhibition of a receptor can have a long-lasting effect on subsequent responsiveness to drug binding.

Drugs modify cell function by binding to receptors, which can initiate, enhance or diminish signals. The signal transduction pathway includes the receptor and intermediary molecules. Major types of drug receptors include ion channels and G protein-coupled receptors.