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Asymmetric Transmitter Binding Sites of Fetal Muscle Acetylcholine Receptors Shape Their Synaptic Response

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Asymmetric Transmitter Binding Sites of Fetal Muscle Acetylcholine Receptors Shape Their Synaptic Response Asymmetric transmitter binding sites of fetal muscle acetylcholine receptors shape their synaptic response Tapan K. Nayak and Anthony Auerbach1 Department of Physiology and Biophysics, State University of New York, Buffalo, NY 14214 Edited by Jean-Pierre Changeux, Institut Pasteur, Paris, France, and approved July 3, 2013 (received for review May 1, 2013) Neuromuscular acetylcholine receptors (AChRs) have two trans- sites are functionally equivalent, but in the fetal subtype, the α−γ mitter binding sites: at α−δ and either α−γ (fetal) or α–e (adult) site has a higher affinity for ACh and provides more energy for subunit interfaces. The γ-subunit of fetal AChRs is indispensable gating than α−δ/e. Simulations of end plate currents suggest the for the proper development of neuromuscular synapses. We esti- differences in activation properties between e- and γ-AChR that mated parameters for acetylcholine (ACh) binding and gating from may impact synaptic development. single channel currents of fetal mouse AChRs expressed in tissue- cultured cells. The unliganded gating equilibrium constant is smaller Results and less voltage-dependent than in adult AChRs. However, the Definitions and Models. AChRs undergo a global, reversible allo- α−γ binding site has a higher affinity for ACh and provides more steric transition between closed (C) and open channel (O) states. binding energy for gating compared with α−e; therefore, the dili- This complex reaction includes numerous changes in structure ganded gating equilibrium constant at −100 mV is comparable for and dynamics at the binding sites (that set the affinity for ago- both receptor subtypes. The −2.2 kcal/mol extra binding energy nist), side chains and domains throughout the protein (that set from α−γ compared with α−δ and α−e is accompanied by a higher the equilibrium constant), and narrow regions of the pore (that resting affinity for ACh, mainly because of slower transmitter dis- set the ionic conductance). We use “gating” to refer to every- sociation. End plate current simulations suggest that the higher thing that happens in C↔O, either with or without agonists at affinity and increased energy from α−γ are essential for generat- the binding sites. Agonist binding to AChRs is also a complex ing synaptic responses at low pulse [ACh]. reaction that requires both diffusion of the ligand and a change in protein conformation (23). We use “binding” to refer to ev- allostery | cholinergic | nicotinic | kinetics erything that happens in the formation of a liganded complex. The binding and gating energies reported below are the sums of the energy changes for all of the microscopic steps within each of ertebrate neuromuscular acetylcholine receptors (AChRs) these multifaceted processes. are ligand-gated ion channels comprised of five subunits: two V The model used for estimating the parameters is shown in α(1) and one each of β, δ, and either γ or e. In most species, the Fig. 1A. The free energy difference, O vs. C, is ΔG , where n is γ-subunit is replaced by e during postnatal development. Elec- n trical activity in muscle cells induced by the neurotransmitter the number of bound agonists (A). The horizontal arrows rep- resent ligand binding at two sites. The free energy for binding to acetylcholine (ACh) is important for the molecular maturation fi Δ α−γ e α−δ γ e the lower-af nity C state is GLA (either / or ) and the of -to -AChRs (1, 2). fi Δ Δ γ higher-af nity O state is GHA. GB is the net binding free Without -subunit, neuromuscular synapses do not develop Δ = Δ − Δ ΔΔ properly (3) and are abnormal in innervation patterns (4) and energy from each ligand ( GB GHA GLA; really a G). muscle fiber-type composition (5). In mice, the γ-subunit KO is From detailed balance, lethal (6), and in humans, mutations in the cholinergic receptor, Δ = Δ + Δ + Δ : [1] nicotinic, gamma (CHRNG) gene that encodes for γ-subunit are G2 G0 GB1 GB2 associated with lethal forms of multiple pterygium and Escobar – The gating energy with two bound agonists is equal to the in- syndromes (7 9). fi AChRs have two transmitter binding sites located in the ex- trinsic gating energy plus the binding energy from two af nity Δ tracellular domain at α–δ and α–γ/e-subunit interfaces. In adult changes. GB is proportional to the log of the coupling constant Δ AChRs, the α−δ and α−e sites are equal and independent insofar (the C vs. O equilibrium dissociation constant ratio), and G0 is as each has the same affinity for ACh and supplies the same proportional to the log of the allosteric constant (the gating Δ amount of binding energy for gating (10). In fetal AChRs, the equilibrium constant in the absence of agonists). GB is the free fi two binding sites are asymmetric with regard to agonist affinity, energy generated by the af nity change for the agonist at each with estimates for the ratio of resting equilibrium dissociation transmitter binding site that ultimately contributes to the in- constants for ACh ranging from ∼5- (11, 12) to >100-fold (13, creased relative stability of A2O vs. A2C. We estimated binding 14). γ-AChRs also have a longer open channel lifetime, a smaller and gating rate constants from single channel interval durations, + unitary conductance, and a lower Ca2 permeability than equilibrium constants from the rate constant ratios, and energies e-AChRs (15–17). by taking the log of the equilibrium constants [ΔG = −0.59 Fetal AChRs hold a special place in the history of ion channel lnKeq (kcal/mol)]. biophysics. The first single channel recordings from cells were of ΔGWT fi γ-AChRs (18). They were also the first ion channels to be ana- 0 . Our rst step was to estimate the energy difference be- lyzed according to a thermodynamic cycle, which required quan- tween C and O with only water present at the two transmitter tifying constitutive activity in the absence of agonists (19). These pioneering studies of single channel currents from mouse myo- tubes led to the estimate that the unliganded gating equilibrium Author contributions: T.K.N. and A.A. designed research; T.K.N. performed research; T.K.N. − constant of γ-AChRs is ∼1.6 × 10 6. γ-AChRs were also the first and A.A. analyzed data; and T.K.N. and A.A. wrote the paper. channels for which the rate and equilibrium constants for closed The authors declare no conflict of interest. channel binding and liganded gating were measured (13, 20–22). This article is a PNAS Direct Submission. We have used improved methods of analysis to extend these 1To whom correspondence should be addressed. E-mail: [email protected]. γ studies of -AChRs with regard to both the rate constants and This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. thermodynamics of activation. In adult AChRs, the two binding 1073/pnas.1308247110/-/DCSupplemental. 13654–13659 | PNAS | August 13, 2013 | vol. 110 | no. 33 www.pnas.org/cgi/doi/10.1073/pnas.1308247110 Downloaded by guest on October 1, 2021 is +10.5 kcal/mol. Some but not all of the offset in the γ- vs. e-lines in Fig. 2B can be attributed to different voltage sensitiv- ities of the two subtypes. Fig. 2C shows constitutive activity of WT γ-AChRs measured in the absence of agonists at −100 mV. From the distribution of WT = ; ± −1 open interval durations, b0 2 546 635 s (mean open time ∼ μ WT 400 s). E0 is the ratio of the forward/backward gating rate WT = : × −4 −1 constants, and therefore, we calculate that f0 1 32 10 s (each unliganded γ-AChR opens spontaneously about 11 times/d). For comparison, the gating rate constants at −100 mV in e-AChRs Fig. 1. Models and mutations. (A) Front plane is a thermodynamic cycle for WT = × −4 −1 ∼ WT = ; −1 one binding site. Thick lines are the physiological two-site scheme. (B) Side are f0 67 10 s ( 600 times/d) and b0 8 800 s chain substitutions at homologous positions in e- and γ-AChRs are equiva- (meanopentime∼ 110 μs) (Table 2). The γ→e-subunit sub- lent. Plot of ΔΔG2 (kcal/mol) in fetal vs. adult AChRs for 11 different point stitution increases both the forward and backward gating rate mutations (open, choline; filled, ACh). Locations of the residues are shown in constants but to different extents; therefore, the unliganded Fig. S1A. Slope of the regression = 0.93 ± 0.04 (R2 = 0.98). gating equilibrium constant is also increased. ACh ACh ΔG2 and ΔGB . We next measured the total energy from the fi Δ WT binding sites. It is dif cult to estimate G0 directly, because affinity changes for ACh at both the α−δ and α−γ binding sites. without agonists, WT γ-AChRs rarely open. However, by using Δ ACh Our approach was to measure G2 , and then, armed with combinations of background mutations that increase constitutive knowledge to ΔGWT, we calculate ðΔGACh + ΔGAChÞ using Eq. 1. Δ WT 0 B1 B2 activity, it is possible to estimate G0 by extrapolation (24, 25). At high [ACh], intracluster activity reflects mainly A C↔A O Δ 2 2 If the only effect of each mutation is to make G0 less positive gating. To facilitate gating rate constant measurements, we (more favorable for opening) and if each mutation acts inde- depolarized the membrane to +70 mV (to reduce channel block Δ WT pendently, then G0 can be estimated from measurements of by the agonist) and added background mutations that increased ΔΔ ACh ACh their effects on the energy of diliganded gating ( G2).
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