Neurotransmitter receptors of the Cys-loop superfamily mediate rapid synaptic transmission throughout the nervous system, and include receptors activated by ACh, GABA, glycine and serotonin. They are involved in physiological processes, including learning and memory, and in neurological disorders, and they are targets for clinically relevant drugs. Cys-loop receptors assemble either from five copies of one type of subunit, giving rise to homomeric receptors, or from several types of subunits, giving rise to heteromeric receptors. Homomeric receptors are invaluable models for probing fundamental relationships between structure and function. Receptors contain a large extracellular domain that carries the binding sites and a transmembrane region that forms the ion pore. How the structural changes elicited by agonist binding are propagated through a distance of 50Å to the ion channel gate is central to understanding receptor function. Depending on the receptor subtype, occupancy of either two, as in the prototype muscle nicotinic receptor, or three binding sites, as in homomeric receptors, is required for full activation. The conformational changes initiated at the binding sites are propagated to the gate through the interface between the extracellular and transmembrane domains. This region forms a network that relays structural changes from the binding site towards the pore, and also contributes to open channel lifetime and rate of desensitization. Thus, this coupling region controls the beginning and duration of a synaptic response. Here we review recent advances in the molecular mechanism by which Cys-loop receptors are activated with particular emphasis on homomeric receptors.
"Many of these channel blockers exert their effects by plugging the channel pore and inhibiting the flow of ions. For several decades channel blockers such as these have been highly instrumental in determining channel pore dimensions, identifying channel-lining residues, and in single channel studies (for recent reviews, see Bouzat, 2012; Sine, 2012). In 1977, Adams first demonstrated that pore blockers can bind both in open and closed channel states, as described for procaine blockade of the nACh receptor at the neuromuscular endplate (Adams, 1977). "
[Show abstract][Hide abstract] ABSTRACT: Pentameric ligand-gated ion channels (pLGIC) catalyze the selective transfer of ions across the cell membrane in response to a specific neurotransmitter. A variety of chemically diverse molecules, including the Alzheimer's drug memantine, block ion conduction at vertebrate pLGICs by plugging the channel pore. We show that memantine has similar potency in ELIC, a prokaryotic pLGIC, when it contains an F16'S pore mutation. X-ray crystal structures, using both memantine and its derivative, Br-memantine, reveal that the ligand is localized at the extracellular entryway of the channel pore, and the pore is in a more closed conformation than wild-type ELIC in both the presence and absence of memantine. However, using voltage clamp fluorometry we observe fluorescence changes in opposite directions during channel activation and pore block, revealing an additional conformational transition not apparent from the crystal structures. These results have important implications for drugs such as memantine, which block channel pores.
"Several loops at the interface between the ABD and the TMD are key to the allosteric transition that links the ABD to the channel gate (Andersen et al., 2011; Bouzat et al., 2004, 2008; Chakrapani et al., 2004; Grutter et al., 2005; Jha et al., 2007; Kash et al., 2003; Lee et al., 2009; Lee and Sine, 2005; Reeves et al., 2005; Shen et al., 2003; Xiu et al., 2005), as reviewed elsewhere (Bouzat, 2012). The ABD is linked covalently to the TMD by a loop between b10 and M1. "
[Show abstract][Hide abstract] ABSTRACT: Pentameric ligand-gated ion channels (pLGICs) mediate fast synaptic communication by converting chemical signals into an electrical response. Recently solved agonist-bound and agonist-free structures greatly extend our understanding of these complex molecular machines. A key challenge to a full description of function, however, is the ability to unequivocally relate determined structures to the canonical resting, open, and desensitized states. Here, we review current understanding of pLGIC structure, with a focus on the conformational changes underlying channel gating. We compare available structural information and review the evidence supporting the assignment of each structure to a particular conformational state. We discuss multiple factors that may complicate the interpretation of crystal structures, highlighting the potential influence of lipids and detergents. We contend that further advances in the structural biology of pLGICs will require deeper insight into the nature of pLGIC-lipid interactions.
"Nicotinic acetylcholine receptors (nAChR) are members of a gene superfamily of ligand-gated ion channels (Albuquerque et al. 2009). These membrane proteins are oligomers composed of five homologous subunits surrounding the ion pore (Bouzat 2012). Different subunits combine to form a variety of receptor subtypes with characteristic functional, pharmacological , and cellular properties (Albuquerque et al. 2009). "
[Show abstract][Hide abstract] ABSTRACT: Although α7 nicotinic receptors are predominantly homopentamers, previous reports have indicated that α7 and β2 subunits are able to form heteromers. We have studied whether other nicotinic receptor subunits can also assemble with α7 subunits and the effect of this potential association. Coexpression of α7 with α2, α3, or β4 subunits reduced to about half, surface α-bungarotoxin binding sites and acetylcholine-gated currents. This is probably because of inhibition of membrane trafficking, as the total amount of α7 subunits was similar in all cases and a significant proportion of mature α7 receptors was present inside the cell. Only β4 subunits appeared to directly associate with α7 receptors at the membrane and these heteromeric receptors showed some kinetic and pharmacological differences when compared with homomeric α7 receptors. Finally, we emulated the situation of bovine chromaffin cells in Xenopus laevis oocytes by using the same proportion of α3, β4, α5, and α7 mRNAs, finding that α-bungarotoxin binding was similarly reduced in spite of increased currents, apparently mediated by α3β4(α5) receptors.
Journal of Neurochemistry 08/2012; 123(4):504-14. DOI:10.1111/j.1471-4159.2012.07931.x · 4.28 Impact Factor
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