Receptor Activity

Cell Surface Receptors:

• 3 classes of cell surface receptors:

• G protein coupled receptors - interact with specific G proteins in plasma membranes - activating or inhibiting enzymes/ion channels

• Most common way for membrane receptors to transmit information into cells
• G protein receptors can amplify extracellular signals

• Ligand-gated ion channels
• Receptor linked enzymes

• These bind extracellular signalling molecules and convert their information into intracellular signals

Guanine Nucleotide Protein Coupled Receptors

• Essential cell communication intermediaries - involved in the molecular mechanisms of countless drugs

• Have an extracellular amino terminus with glycosylation sites, an intracellular carboxyl terminus and a fatty acid attachment
• Three extracellular loops, four intracellular loops
• In 3D view, have transmembrane domains surrounding a binding pocket
• G protein hydrolysis occurs using energy from GTP -> GDP
• Some G proteins are stimulating and some are inhibitory

• Ligand-activated receptor causes activation of a specific G protein
• Guanosine triphosphate hydrolysis to guanosine diphosphate provides energy for the activated G protein to interact with the effector molecule
• Effector enzyme system can be activated or inhibited, and ion channel can be opened or closed in response to G protein activation
• Adrenergic, opioid, muscarinic, cholinergic, dopamine and histamine receptors are all G protein coupled

Second Messenger G-protein Link

• Adenylyl Cyclase system - stimulatory G protein receptor-hormone complexes increase activity of adenylyl cyclase, producing increased levels of cAMP in the cell

• cAMP activates protein kinases that phosphorylate various proteins, ion channels and second messenger systems

• Phosphatidylinositol System

• Another second messenger system - hydrolysis of PIP₂ in the cell membrane, catalyzed by activation of phospholipase C generates IP₃ and DAG
• IP₃ then mobilises intracellular calcium from non-mitochondrial intracellular stores by interacting with distinct IP₃ receptors on the surface of these organelles
• Increase in intracellular calcium levels produces smooth muscle contraction.

Excitable Transmembrane Proteins

• Voltage-Sensitive Ion Channels - open and close in response to changes in voltage across cell membranes

• Closed at normal resting potentials (-60 to -80 mV)
• Voltage-gated ion channels are protein complexes formed by the association of several individual subunits, the largest being the alpha subunit

• Ligand-Gated Ion Channels - include ACh receptors, serotonin receptors, GABA receptors etc

• A pentamer - made up of 5 homologous subunits, each with 4 membrane segments and an extracellular terminus with residues forming neurotransmitter binding sites
• nAChRs and 5HT₃ channels are cation-selective and excitatory - open Na⁺ channels causing depolarization of cell membranes
• GABA_A and Glycine channels are anion-selective and inhibitory - open Cl^- channels causing hyperpolarization - preventing depolarisation

• A second family is activated by glutamate - the principal excitatory neurotransmitter in the CNS

• Different combinations of subunits form ligand-gated ion channels activated by NMDA/AMPA/Kainate

• Involved in fast synaptic transmission between excitable cells
• Important targets for drugs during anaesthesia:

• Neuromuscular blockerrs act on nAChRs
• Barbituates/benzodiazepines act on GABA_A receptors
• Ketamine acts on NMDA receptors

• Transmembrane Receptors

• Interact selectively with extracellular compounds - drugs/hormones/neurotransmitters
• Can bind hydrophilic ligands located in the extracellular space, therefore extracellular drugs do not have to cross lipid bilayers to interact with cells
• Intracellular signal transduction occurs, often by G protein mechanisms

GABA Gamma-Aminobutyric Acid Receptors

• The major inhibitory neurotransmitter of the mammalian brain
• Benzodiazepines, barbituates and propofol enhance GABA mediated inhibition in the CNS

• Increase agonist affinity for GABA_A receptors
• Prolong/augment chloride conductance (which is gated by these receptors)
• Both of these cause CNS depression

• GABA agonists are usually mixed with opioids etc. which provide inhibition of presynaptic calcium ion channels responsible for activating transmitter release
• Volatile anaesthetics probably have a combination effect of activating GABA_A channels as well as decreasing calcium influx

Glycine Receptors

• Closely related to GABA_A receptors
• Inhibitory receptors, selectively permeable to anions, mediate rapid inhibitory synaptic transmission primarily in the spinal cord
• Homonomers of alpha subunits, with activity enhanced by volatile anaesthetics

• 5HT Receptors - all are G-protein coupled other than 5HT₃. These are selectively permeable to cations and have anxiolysis, analgesia and emetic effects
• Glutamate Receptors - an excitatory neurotransmitter with widely expressed receptors. AMPA receptors mediate fast excitatory transmission at most synapses in the CNS

Nucleic Acid Synthesis:

• Nuclear hormone receptors - transcription factors regulating the expression of genes controlling many physiological processes
• Include receptors for androgens, estrogens, glucocorticoids, thyroid hormone etc.
• In the inactive state, receptors for steroids like glucocorticoids reside in the cytoplasm, translocating into the nucleus upon binding ligand
• Made up of 4 domains in a single polypeptide chain

Receptor Concentration

• Receptor concentration in cell membranes is dynamic - either increasing or decreasing in response to specific stimuli
• An excess of endogenous ligand can result in a decrease in the concentration of receptors - causing tachyphylaxis
• An excess of antagonist can result in an increased number of receptors in cell membranes - causing hypersensitivity