A.L. Blatz and K.L. Magleby (1986a. J. Physiol. [Lond.]. 378:141-174) have demonstrated the usefulness of plotting histograms with a logarithmic time axis to display the distributions of dwell times from recordings of single ionic channels. We derive here the probability density function (pdf) corresponding to logarithmically binned histograms. Plotted on a logarithmic time scale the pdf is a peaked function with an invariant width; this and other properties of the pdf, coupled with a variance-stabilizing (square root) transformation for the ordinate, greatly simplify the interpretation and manual fitting of distributions containing multiple exponential components. We have also examined the statistical errors in estimation, by the maximum-likelihood method, of kinetic parameters from logarithmically binned data. Using binned data greatly accelerates the fitting procedure and introduces significant errors only for bins spaced more widely than 8-16 per decade.

The congenital myasthenic syndromes are diverse disorders linked by abnormal signal transmission at the motor endplate that stem from defects in single or multiple proteins. Multiple endplate proteins are affected by mutations of single enzymes required for protein glycosylation, and deletion of PREPL exerts its effect by activating adaptor protein 1. Finally, neuromuscular transmission is also impaired in some congenital myopathies. The specific diagnosis of some syndromes is facilitated by clinical clues pointing to a disease gene. In absence of such clues, exome sequencing is a useful tool for finding the disease gene. Deeper understanding of disease mechanisms come from structural and in vitro electrophysiologic studies of the patient endplate, and from engineering the mutant and wild-type gene into a suitable expression system that can be interrogated by appropriate electrophysiologic and biochemical studies. Most CMS are treatable. Importantly, however, some medication beneficial in one syndrome can be detrimental in another.

Throughout the nervous system, moment-to-moment communication relies on postsynaptic receptors to detect neurotransmitters and change the membrane potential. For the Cys-loop superfamily of receptors, recent structural data have catalysed a leap in our understanding of the three steps of chemical-to-electrical transduction: neurotransmitter binding, communication between the binding site and the barrier to ions, and opening and closing of the barrier. The emerging insights might be expected to explain how mutations of receptors cause neurological disease, but the opposite is generally true. Namely, analyses of disease-causing mutations have clarified receptor structure-function relationships as well as mechanisms governing the postsynaptic response.

Synaptic receptors respond to neurotransmitters by opening an intrinsic ion channel in the final step in synaptic transmission. How binding of the neurotransmitter is conveyed over the long distance to the channel remains a central question in neurobiology. Here we delineate a principal pathway that links neurotransmitter binding to channel gating by using a structural model of the Torpedo acetylcholine receptor at 4-A resolution, recordings of currents through single receptor channels and determinations of energetic coupling between pairs of residues. We show that a pair of invariant arginine and glutamate residues in each receptor alpha-subunit electrostatically links peripheral and inner beta-sheets from the binding domain and positions them to engage with the channel. The key glutamate and flanking valine residues energetically couple to conserved proline and serine residues emerging from the top of the channel-forming alpha-helix, suggesting that this is the point at which the binding domain triggers opening of the channel. The series of interresidue couplings identified here constitutes a primary allosteric pathway that links neurotransmitter binding to channel gating.

Neurotransmitter receptors from the Cys-loop superfamily couple the binding of agonist to the opening of an intrinsic ion pore in the final step in rapid synaptic transmission. Although atomic resolution structural data have recently emerged for individual binding and pore domains, how they are linked into a functional unit remains unknown. Here we identify structural requirements for functionally coupling the two domains by combining acetylcholine (ACh)-binding protein, whose structure was determined at atomic resolution, with the pore domain from the serotonin type-3A (5-HT3A) receptor. Only when amino-acid sequences of three loops in ACh-binding protein are changed to their 5-HT3A counterparts does ACh bind with low affinity characteristic of activatable receptors, and trigger opening of the ion pore. Thus functional coupling requires structural compatibility at the interface of the binding and pore domains. Structural modelling reveals a network of interacting loops between binding and pore domains that mediates this allosteric coupling process.