Successive openings of the same acetylcholine receptor channel are correlated in open time

Jackson, Meyer B.; Wong, B.S.; Morris, Catherine E.; Lecar, Harold; Christian, Clifford

doi:10.1016/s0006-3495(83)84375-6

Cited by 164 publications

(152 citation statements)

References 18 publications

Supporting

Mentioning

143

Contrasting

Order By: Relevance

“…This prediction was borne out by their experimental results, using a-bungarotoxin to reduce the effective concentration of ACh receptors (Land et al 1981). In addition, both Land et al (1984) and Wathey et al (1979) (Sakmann, 1978;Jackson, Wong, Morris, Lecar & Christian, 1983 …”

Section: Methodsmentioning

confidence: 99%

The difference in shape of spontaneous and uniquantal evoked synaptic potentials in frog muscle.

Cherki-Vakil

Ginsburg

Meiri

1995

The Journal of Physiology

View full text Add to dashboard Cite

3. The difference did not stem from changes in the muscle membrane conductance or from inclusion of outstanding MEPPs0 formed as a result of the block of acetylcholinesterase.4. The dependence of the rise time on the amplitude was also stronger in MEPPs. than in EPPso. 5. In the absence of neostigmine, MEPPso exhibited a positive correlation between decay time constant and amplitude, while EPPso did not show such a correlation.6. In view of previously published models of transmitter release, it is suggested that spontaneous secretion of quanta occurs both within and outside the active zones facing postsynaptic areas of variable receptor density.The quantal hypothesis of transmitter release suggested 40 years ago for the frog motor synapse states that miniature endplate potentials (MEPPs) and stimulationinduced endplate potentials (EPPs) both result from secretion of prepacked quanta of acetylcholine (ACh) from the motor nerve ending. EPPs are induced by several quanta released almost synchronously, and MEPPs by individual spontaneously secreted quanta (del Castillo & Katz, 1954). To the best of our knowledge, the idea that MEPPs and EPPs originate at the same location on the muscle membrane and result from secretion of similar quanta of transmitter has never been challenged. This view is most probably due to their formal resemblance in shape and their comparable sensitivities to muscle membrane potential and to pharmacological agents (Fatt & Katz, 1952; Magleby & Stevens, 1972 a, b). On the other hand, the discovery of 'giant MEPPs', which do not participate in the formation of EPPs, suggests that not all quanta available for spontaneous secretion are suitable for release upon nerve stimulation (Liley, 1956;Pecot-Dechavassine, 1976

show abstract

Section: Methodsmentioning

confidence: 99%

The difference in shape of spontaneous and uniquantal evoked synaptic potentials in frog muscle.

Cherki-Vakil

Ginsburg

Meiri

1995

The Journal of Physiology

View full text Add to dashboard Cite

show abstract

“…Until now, studies of CFTR gating have focused on extracting open probability and average τ b and τ ib , which are readily obtained from patches containing either single (34,35) or multiple (36) channels. Fig.…”

Section: Perturbations That Profoundly Alter the Mechanism Of Gating mentioning

confidence: 99%

Strict coupling between CFTR’s catalytic cycle and gating of its Cl ⁻ ion pore revealed by distributions of open channel burst durations

Csanády

Vergani

Gadsby

2009

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

114

221

View full text Add to dashboard Cite

CFTR, the ABC protein defective in cystic fibrosis, functions as an anion channel. Once phosphorylated by protein kinase A, a CFTR channel is opened and closed by events at its two cytosolic nucleotide binding domains (NBDs). Formation of a head-to-tail NBD1/NBD2 heterodimer, by ATP binding in two interfacial composite sites between conserved Walker A and B motifs of one NBD and the ABC-specific signature sequence of the other, has been proposed to trigger channel opening. ATP hydrolysis at the only catalytically competent interfacial site is suggested to then destabilize the NBD dimer and prompt channel closure. But this gating mechanism, and how tightly CFTR channel opening and closing are coupled to its catalytic cycle, remains controversial. Here we determine the distributions of open burst durations of individual CFTR channels, and use maximum likelihood to evaluate fits to equilibrium and nonequilibrium mechanisms and estimate the rate constants that govern channel closure. We examine partially and fully phosphorylated wild-type CFTR channels, and two mutant CFTR channels, each bearing a deleterious mutation in one or other composite ATP binding site. We show that the wild-type CFTR channel gating cycle is essentially irreversible and tightly coupled to the ATPase cycle, and that this coupling is completely destroyed by the NBD2 Walker B mutation D1370N but only partially disrupted by the NBD1 Walker A mutation K464A.ATPase cycle | maximum likelihood | nonequilibrium | phosphorylation | Walker motifsA TP-binding cassette (ABC) proteins bind and hydrolyze ATP, usually to power transport of substrates across membranes. Their common architecture comprises two transmembrane domains (TMDs) and two cytoplasmic nucleotide binding domains (NBDs) containing conserved sequences for interacting with ATP. Once ATP binds to the conserved Walker A and B motifs of each NBD, they dimerize in head-to-tail fashion, burying two ATP molecules in composite interfacial sites (1, 2). Cyclic formation and disruption of the dimer requires hydrolysis of at least one of the ATPs per cycle (3-6).The ion channel CFTR contains, in addition to canonical ABC protein domains (TMD1, NBD1, TMD2, NBD2), a unique regulatory (R) domain (7) with multiple cAMP-dependent protein kinase (PKA) targets that must be phosphorylated for ATP to activate bursts of channel openings reviewed in ref. 8). But the mechanism of CFTR channel gating remains controversial. Early observations that the gating pattern violates microscopic reversibility suggested that the process underlying bursting operates far from thermodynamic equilibrium (9-11). Building on this, with functional evidence from mutants and nucleotide homologs (12-15) and with structural and biochemical data from prokaryotic NBDs (1-4), a CFTR channel open burst was proposed to be initiated by ATP-mediated formation of a stable NBD1-NBD2 heterodimer, and terminated by dimer dissociation after ATP hydrolysis (16). The ATP hydrolysis was posited to occur at the NBD2 composite site (between NBD2 Walke...

show abstract

“…The four fastest time constants were classified as being within-bursts if they were similar across different patches at the same concentration and across different concentrations (Table 1). Thus, a t crit value of 4 ms was chosen between the fourth and fifth shut time component, using the criterion of minimizing the total number of misclassified events (Jackson et al, 1983). The progressive shortening at higher glycine concentrations of the longer (interburst) shut times is clearly visible in the distributions in Figure 1, right-hand column, and in the expanded traces shown in Figure 2 (A-E).…”

Section: Experimental Dwell-time Distributionsmentioning

confidence: 99%

Single-Channel Behavior of Heteromeric α1β Glycine Receptors: An Attempt to Detect a Conformational Change before the Channel Opens

Burzomato¹,

Beato²,

et al. 2004

View full text Add to dashboard Cite

An alternative, and novel, explanation is that agonist binding stabilizes a higher affinity form of the receptor that is produced by a conformational change ("flip") that is separate from, and precedes, channel opening. Both the "interaction" scheme and the flip scheme describe our data well, but the latter has fewer free parameters and above all it offers a mechanism for the affinity increase. Distinguishing between the two mechanisms will be important for our understanding of the structural dynamics of activation in the nicotinic superfamily and is important for our understanding of mutations in these receptors.

show abstract

Successive openings of the same acetylcholine receptor channel are correlated in open time

Cited by 164 publications

References 18 publications

The difference in shape of spontaneous and uniquantal evoked synaptic potentials in frog muscle.

The difference in shape of spontaneous and uniquantal evoked synaptic potentials in frog muscle.

Strict coupling between CFTR’s catalytic cycle and gating of its Cl ⁻ ion pore revealed by distributions of open channel burst durations

Single-Channel Behavior of Heteromeric α1β Glycine Receptors: An Attempt to Detect a Conformational Change before the Channel Opens

Contact Info

Product

Resources

About

Successive openings of the same acetylcholine receptor channel are correlated in open time

Cited by 164 publications

References 18 publications

The difference in shape of spontaneous and uniquantal evoked synaptic potentials in frog muscle.

The difference in shape of spontaneous and uniquantal evoked synaptic potentials in frog muscle.

Strict coupling between CFTR’s catalytic cycle and gating of its Cl − ion pore revealed by distributions of open channel burst durations

Single-Channel Behavior of Heteromeric α1β Glycine Receptors: An Attempt to Detect a Conformational Change before the Channel Opens

Contact Info

Product

Resources

About

Strict coupling between CFTR’s catalytic cycle and gating of its Cl ⁻ ion pore revealed by distributions of open channel burst durations