Receptor Activity

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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
  • GABAA 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 GABAA 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 GABAA 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 GABAA channels as well as decreasing calcium influx

Glycine Receptors

  • Closely related to GABAA 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