Compare and contrast the structure and function of ligand gated ion channels and GPCRs PDF

Preview

Summary

Compare and contrast the structure and function of ligand gated ion channels and GPCRs...

Description

Compare and contrast the structure and function of ligand gated ion channels and G-protein coupled receptors. Structural patterns and associated transduction pathways follow similar patterns between receptors although differences are observed as well. Ligand-gated ion channels are typically found at skeletal neuromuscular junctions and are acted on by fast neurotransmitters such as acetyl choline whereas G-protein coupled receptors (GPCRs) are more abundant, in fact the human genome encodes roughly 400 different GPCRs. These receptors are acted on by slower acting neurotransmitters such as dopamine and serotonin. The response of a ligand-gated ion channel occurs in milliseconds whereas in a GPCR it is within seconds due to the coupling mechanism adding extra complexity to elicit a response meaning GPCRs are slower to respond to a signal. There are a variety of differences observed in the structures of these receptors despite both being membrane receptors and both have an extracellular N-terminus binding domain. Ligand-gated ion channels have a pentameric structure consisting of four different subunits; α,β,γ,δ each of which has a molecular weight of 40-58 kDa. The structure consists of 4 or 5 transmembrane domains. Each subunit spans the membrane four times meaning the channel is composed of around 20 membrane spanning helices which surround the central pore. The structure possesses two ACh binding sites which lie on either side of the two α-subunits. Both binding sites must be bound to activate the receptor. The structure of the GPCR differs in that the receptor consists of a single polypeptide chain which is usually comprised of 350-400 residues, but this can be up to 1100 residues. The GPCR has only 7 transmembrane α-helices compared to the 20 or so present in ligand-gated ion channels. They have an extracellular N terminus and an intracellular C terminus whereas in ligand-gated ion channels these are both extracellular. The differences between the various GPCR families is primarily in the length of the extracellular N-terminus and the location of the agonist binding site. The third cytoplasmic loop of GPCRs are important to their function as they have a key role in coupling the Gprotein to the receptor. This was discovered as deletion or modification of this region resulted in receptors which could still bind ligands however they could not associate with the G-protein and therefore could not produce a response. The G-protein is anchored to the membrane through attached lipid residues. It is a trimer consisting of 3 subunits α,β,γ, guanine nucleotides bind to the αsubunit, which has enzymatic GTPase activity. G proteins are freely diffusible in the plane of the membrane and so can interact with several different receptors. Differences are also observed in the mechanisms of action of these receptors. Ligand-gated ion channels possess a gating mechanisms. One of the transmembrane helices (M 2) from each of the 5 subunits forms the lining of the channel. The five M2 helices that form the pore have sharp kinks that point inwards within the channel blocking it. When two molecules of ACh bind it causes a conformational change in the extracellular part of the receptor which twists the α-subunits which swivels the kinked M 2 regions out of the way opening the channel. The channel is also lined with a series of anionic residues which makes it selectively permeable to cations; primarily Na+ and K+ although sometimes also Ca2+. The mechanism of the GPCR is very different. When a ligand binds to a GPCR a conformational change occurs involving the cytoplasmic domain of the receptor. This conformational change increases the affinity for the G-protein. When the G-protein is associated with the receptor it causes bound GDP in the α-subunit to be displaced with GTP. The α-subunit then dissociates from the βγ subunits, these are the active forms of the G-protein and can associate with effector proteins. Both the α and βγ subunits can function to control effectors. This activation results in signal amplification as a single ligand can activate several G-proteins each of these can associate with the effector

enzyme to produce many molecules which is usually a ‘second messenger’. When the α-GTP subunit interacts with its target its GTPase activity is increased, the level of increase is dependent on the effector, leading to hydrolysis of the bound GTP back to GDP. When this occurs the α subunit recombines with the βγ subunit. The activation of the effector is therefore self-limiting. It is the molecular variation in the α-subunit that allows for the specificity of the G-protein for its target. The four main classes of G-protein are G s, Gi, Go and Gq. These show selectivity to both the receptors and effectors which they couple to. Gs and Gi produce stimulatory and inhibitory effects on adenylyl cyclase. This specificity is important in the function of GPCRs. In conclusion, there are general similarities between the two different receptors however differences are observed between the structure and mechanism of action. Both receptors are important targets for drugs. Drugs such as tubocurarine target the nicotinic ACh receptor, which is a ligand-gated ion channel, inhibiting it to relax skeletal muscle during surgery. GPCRs are also targeted such as the β2 adrenoreceptor which is targeted by salbutamol which is a agonist of the receptor and leads to bronchodilation, it is used in the treatment of asthma....