BS2550 - Neuronal and Cellular Signalling Lecture 7 Ionotropic and Metabotropic Receptors Ionotropic receptors contain a ligand binding site and an ion channel. The door is the receptor, the key is the neurotransmitter, and the key slot is the binding site. Metabotropic receptors have no ion channels and affect nearby ion channels via intracellular secondary messengers (most commonly via G-proteins). Their physiologies are very different: transmitter EXTRACELLULAR lonotropic receptor INTRACELLULAR lonotropic receptor Metabotropic receptor metabotropic receptor intracellular second messenger ion channel EXTRACELLULAR INTRACELLULAR Ionotropic (ligand-gated) receptors mediate rapid postsynaptic effects (1-2ms post AP) that are short- lasting (<1ms). Ligands include -> neurotransmitters like ACh, glutamate, GABA, serotonin, glycine -> drugs like nicotine (nAChRs), muscarine, a compound present in fungi (mAChRs), receptors are named after the agonists that activate them. Ligands can bind to multiple receptors. Acetylcholine (ACh) binds to muscarinic (mAChR) and nicotinic (nAChR) ACh receptors, nicotinic receptors are usually found on skeletal muscle or a postganglionic neuron and muscarinic ones are found on target tissues and these are metabotropic. nAChR (ionotropic) motoneurone skeletal muscle Parasympatheticbranch of the autonomicnervous system nAChR (ionotropic) mAChR (metabotropic) target tissue pre-ganglionic neurone post-ganglionic neurone There are three superfamilies of ionotropic receptors: - Cys-loop receptors -> these are pentameric (daĆ[]8) and contain four transmembrane domains each. There are also 2 ligand-binding sites and these are primarily ACh/serotonin receptors - lonotropic glutamate receptors -> these are tetrameric (composed of ft subunits) and also have ft transmembrane domains each with ft agonist-binding sites. These receptors also called NMDA, AMPA receptors - ATP-gated receptors -> these are trimeric and contain two TM domains each with three ligand-binding sites. They are sometimes called P2X receptors, these mediate contraction during ejaculation and urination as they are found in the urinary tract.
There are 16 genes that code for nAChRs in the human genome that bind ACh, 7 code for NMDA receptors that bind glutamate, ft genes code for AMPA receptors that also binds glutamate and 7 genes that code for other receptors which glutamate binds to. 19 genes code for GABAA receptors that bind GABA. Glycine binds to glycine receptors coded for by 5 genes, ATP is bound to P2X receptors of which there are 7 genes in the human genome that code for them. Nicotinic AChR Widely expressed in the muscular and nervous system (brain, sympathetic and parasympathetic ganglia), they mediate fast synaptic transmission. Fetal AChR is expressed at the NMJ; replaced by the adult form from about 30 weeks gestation. NMJ- associated nAChRs -> postsynaptic (muscle) nAChR are involved in classical neurotransmission and presynaptic (neuronal) nAChR are involved in the modulation of neurotransmitter release. Structure and activation of nACh receptors -> ACh binding to the alpha subunits of nACh receptors induces conformational changes (pulling apart of alpha helices) in the transmembrane segments of the receptor complex, exposing (opening) the ion pore. There are individual channels which stay open for varying durations and they are involved in the all- or-none response. To show this you can use patch clamp