Activation of the primary kinetic modes of large‐ and small‐conductance cholinergic ion channels in Xenopus myocytes.

Auerbach, Anthony; Lingle, Christopher J.

doi:10.1113/jphysiol.1987.sp016832

Cited by 31 publications

(39 citation statements)

References 41 publications

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“…In adult AChRs, the α−δ and α−e sites are equal and independent insofar as each has the same affinity for ACh and supplies the same amount of binding energy for gating (10). In fetal AChRs, the two binding sites are asymmetric with regard to agonist affinity, with estimates for the ratio of resting equilibrium dissociation constants for ACh ranging from ∼5- (11,12) to >100-fold (13,14). γ-AChRs also have a longer open channel lifetime, a smaller unitary conductance, and a lower Ca 2+ permeability than e-AChRs (15)(16)(17).…”

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confidence: 99%

Asymmetric transmitter binding sites of fetal muscle acetylcholine receptors shape their synaptic response

Nayak

Auerbach

2013

Proc. Natl. Acad. Sci. U.S.A.

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Neuromuscular acetylcholine receptors (AChRs) have two transmitter binding sites: at α−δ and either α−γ (fetal) or α-e (adult) subunit interfaces. The γ-subunit of fetal AChRs is indispensable for the proper development of neuromuscular synapses. We estimated parameters for acetylcholine (ACh) binding and gating from single channel currents of fetal mouse AChRs expressed in tissuecultured cells. The unliganded gating equilibrium constant is smaller and less voltage-dependent than in adult AChRs. However, the α−γ binding site has a higher affinity for ACh and provides more binding energy for gating compared with α−e; therefore, the diliganded gating equilibrium constant at −100 mV is comparable for both receptor subtypes. The −2.2 kcal/mol extra binding energy from α−γ compared with α−δ and α−e is accompanied by a higher resting affinity for ACh, mainly because of slower transmitter dissociation. End plate current simulations suggest that the higher affinity and increased energy from α−γ are essential for generating synaptic responses at low pulse [ACh].are ligand-gated ion channels comprised of five subunits: two α(1) and one each of β, δ, and either γ or e. In most species, the γ-subunit is replaced by e during postnatal development. Electrical activity in muscle cells induced by the neurotransmitter acetylcholine (ACh) is important for the molecular maturation of γ-to e-AChRs (1, 2).Without γ-subunit, neuromuscular synapses do not develop properly (3) and are abnormal in innervation patterns (4) and muscle fiber-type composition (5). In mice, the γ-subunit KO is lethal (6), and in humans, mutations in the cholinergic receptor, nicotinic, gamma (CHRNG) gene that encodes for γ-subunit are associated with lethal forms of multiple pterygium and Escobar syndromes (7-9).AChRs have two transmitter binding sites located in the extracellular domain at α-δ and α-γ/e-subunit interfaces. In adult AChRs, the α−δ and α−e sites are equal and independent insofar as each has the same affinity for ACh and supplies the same amount of binding energy for gating (10). In fetal AChRs, the two binding sites are asymmetric with regard to agonist affinity, with estimates for the ratio of resting equilibrium dissociation constants for ACh ranging from ∼5-(11, 12) to >100-fold (13, 14). γ-AChRs also have a longer open channel lifetime, a smaller unitary conductance, and a lower Ca 2+ permeability than e-AChRs (15-17).Fetal AChRs hold a special place in the history of ion channel biophysics. The first single channel recordings from cells were of γ-AChRs (18). They were also the first ion channels to be analyzed according to a thermodynamic cycle, which required quantifying constitutive activity in the absence of agonists (19). These pioneering studies of single channel currents from mouse myotubes led to the estimate that the unliganded gating equilibrium constant of γ-AChRs is ∼1.6 × 10 −6 . γ-AChRs were also the first channels for which the rate and equilibrium constants for closed channel binding and liganded gating were measured (13,(...

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confidence: 99%

Asymmetric transmitter binding sites of fetal muscle acetylcholine receptors shape their synaptic response

Nayak

Auerbach

2013

Proc. Natl. Acad. Sci. U.S.A.

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“…5), as observed for the 40 pS channels in myotomal muscle (Auerbach and Lingle, 1987;Igusa and Kidokoro, 1987;Owens and Kullberg, 1989). The fast component had a mean time constant of 0.39 f 0.12 msec (11) and constituted about 27% of the events (average of all 3 muscles, at 40 mV applied potential).…”

Section: Gating Kineticsmentioning

confidence: 81%

“…The remaining histograms appeared to have distinct fast and slow components and were fitted better by double-exponential functions, with mean time constants of 0.62 + 0.38 and 4.23 f 1.86 msec (n = 9 sites, at 40 mV applied potential). In this respect, the 25 pS channels also resemble the 40 pS channels, which frequently have double-exponential open duration histograms (Brehm et al, 1984a, b;Auerbach and Lingle, 1987;Igusa and Kidokoro, 1987;Leonard et al, 1988;Owens and Kullberg, 1989). In our measurements of channel open times, data were pooled from the 3 different muscles, since we did not notice any major differences between them.…”

Section: Gating Kineticsmentioning

confidence: 99%

“…Recordings with high [AChJ When the recording pipette contained high [ACh] (20 or 50 WM) channel openings occurred in bursts of many events, separated by long periods of silence, typical of desensitized AChRs (Sakmann et al, 1980;Auerbach and Lingle, 1987;Igusa and Kidokoro, 1987). Bursts of all 3 conductance classes were observed, sometimes within the same record as shown in Figure 6.…”

Section: Gating Kineticsmentioning

confidence: 99%

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Three conductance classes of nicotinic acetylcholine receptors are expressed in developing amphibian skeletal muscle

Owens

Kullberg

1989

J. Neurosci.

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Two previously described classes of nicotinic AChRs in vertebrate skeletal muscle have conductances of 40 and 60 pS. In addition, a third conductance class of AChR channels is present in developing Xenopus muscle. This class appears to represent an independent channel type, rather than a subconductance state of the larger conductance channels. The channel has a slope conductance of 25 pS and a reversal potential of about 0 mV membrane potential. Its kinetic properties resemble those of the 40 pS channels present in early embryonic myotomal muscle. The channel has a mean open time of about 6 msec (at 40 mV applied potential). The open time is dependent on membrane potential and increases e-fold for every 60 mV of hyperpolarization. Consecutive openings were often separated by brief closures of about 0.4 msec in duration. The identity of the channel as a nicotinic AChR was established by blocking the channel openings with alpha-BTX and by demonstrating bursting and desensitization in the presence of high agonist concentrations. In some muscles (e.g., extraocular), this channel may be a predominant form at early developmental stages and could therefore be important to the function of developing synapses in those muscles.

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“…The kinetic properties of the predominant, fetal-type cholinergic channel (Auerbach & Lingle, 1987) were analysed by the Horn & Lange (1983) maximum-likelihood method. This involves computing the likelihood of observing the experimental data given a kinetic model and adjusting the parameters of the model until the likelihood is maximal (until the -log likelihood is at a minimum).…”

Section: A]t = [A][1 + 27((-i)' Exp (-N2t/t)] Andmentioning

confidence: 99%

A statistical analysis of acetylcholine receptor activation in Xenopus myocytes: stepwise versus concerted models of gating.

Auerbach

1993

The Journal of Physiology

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5. In eighteen of twenty-seven file-by-file comparisons, the likelihood of the stepwise model was greater than that of the concerted model. In seven such comparisons, the likelihood of the concerted model was greater than that of the stepwise model, and in two there was no difference. Log likelihood ratio distributions were obtained from three files (those with the most events) by multiple cycles of resampling and fitting. The means of these distributions were significantly greater than zero, indicating that the stepwise scheme was as good as, or better than. the concerted scheme in describing receptor activation. activation predicts that the decay of the endplate current is determined by five rates.

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Activation of the primary kinetic modes of large‐ and small‐conductance cholinergic ion channels in Xenopus myocytes.

Cited by 31 publications

References 41 publications

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

Three conductance classes of nicotinic acetylcholine receptors are expressed in developing amphibian skeletal muscle

A statistical analysis of acetylcholine receptor activation in Xenopus myocytes: stepwise versus concerted models of gating.

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