Lecture 9: Ionotropic Receptors Main Features: - Contain a ligand binding site and an ion channel o In response to a ligand binding, they undergo a conformational change -> initiating a sequence of events intracellularly - Ligands: can bind to multiple receptors o Neurotransmitter: ACh, Glutamate, GABA, Serotonin and Glycine o Drugs: nicotine (nAChRs), muscarine (mAChRs) o Receptors are named after the agonists that activate them Superfamilies of ionotropic receptors 1. Cys-loop receptors -> Examples: ACh + serotonin receptors - Pentameric: Five 4 subunit domains form 1 whole cys-loop receptor - Four TM domains each - Two ligand binding sites 2. lonotropic glutamate receptors > Examples: NMDA + AMPA receptors ? C EXTRACELLULAR - Tetrameric - Four TM domains each - Four agonist-binding sites INTRACELLULAR surface view: all subunits 3. ATP - gated receptors > Examples: P2X receptors - Trimeric - Two TM domains each - Three ligand- binding sites AChR. GABA,R, GlyR, 5-HT3R ionotropic glutamate receptor nACh Receptor : Typical ligand-gated channel - Widely expressed in the muscular and nervous system (brain, sympathetic and parasympathetic ganglia) - Mediate fast synaptic transmission - Fetal AChR is expressed at the NMJ; replaced by the adult form from about 30 weeks gestation - NMJ-associated nAChRs: ATP-associated P2X receptor o Postsynaptic (muscle) nAChR: classical neurotranmission o Presynaptic (neuronal) nAChR: modulation of neurotransmitter release Structure and activation of nACh Receptors ACh binding sites ACH ACh binding to the a subunits of nACh receptors induces conformational changes in the transmembrane segments of the receptor complex > exposing (opening) the ion pore EXTRACELLULAR 5 ACh binding sites INTRACELLULAR M2 helix Prinoples of Neurobiology (ch.3]
(A) Closed Muscle ACh Receptors have nonselective cation channels: Na+ Na+ Na K+ ACh - AChRs are permeable to both Na+ and K+ - release - Na + influx >> K+ efflux -> leads to depolarisation Na+ 1 + K K+ K K+ Na+ Na Na+ Desensitization of nACh receptors: Open - AChRs can desensitise > an accumulation of receptors in an agonist- bound but non-conducting conformational state - nAChR subtypes are expressed in multiple circuits throughout the brain involved in mood regulation Desensitised 1 - Cigarette smoking (nicotine) acts as an antidepressant through rapid AChRs desensitisation - Transition between various states can be influenced by allosteric modulators ( e.g.kinases) AMPA and NMDA glutamate receptors - Glutamate is the main excitatory neurotransmitter in the nervous system - Majority of synapses in the vertebrate CNS are glutamatergic - All neurons express ionotropic glutamate receptors - Glutamate receptors (GluRs) are permeable to both Na+ and K* generating excitatory postsynaptic potentials (EPSPs) o Not very permeable to Ca2+ - Inward currents are called excitatory postsynaptic currents (EPSC) + + + Na K* K+ AMPA Receptors: - Activated by the agonist AMPA (2-amino- 3-hydroxy-5-methylisoxazol-4-propanoic acid) - Expressed in neurons and glial cells (e.g. in astrocytes) - Promotes depolarisation when the postsynaptic neuron is near the resting potential - Together with kainate receptors, belong to the group of non-NMDA receptors Kainate receptors = ionotropic receptors that respond