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Abstract
The acetylcholine receptor (AcChR) of the mammalian motor end plate or of the electroplaque of certain fishes is a highly regulated membrane glycoprotein responsible for communicating electrical stimuli across the neuroeffector junction. Absolute regulation of the ion conductance properties of this molecule is vital if correct postsynaptic responsiveness to the neurotransmitter acetylcholine is to be maintained.
There is increasing evidence that many factors can contribute to the modulation of AcChR functionality including, but not restricted to, all of the following: (a) a finely-tuned membrane microenvironment including lipid and protein components; (b) binding of various ligand classes (agonists and antagonists) as well as specific snake (alpha)-neurotoxins; (c) as yet undefined neural "trophic factors" which are part of a tightly interwoven neuroeffector connection; and (d) anti-acetylcholine receptor antibodies produced during the autoimmune disease myasthenia gravis. All of these factors can be considered to be biological modulators of the AcChR.
In this work, some of the molecular aspects of the interaction of these various modulators with the AcChR are examined. The first chapter describes a series of studies undertaken to define both the type and magnitude of myasthenic anti-AcChR antibody interference in in situ membrane-bound AcChR function, emphasizing the effect of bound antibody on receptor affinity state transitions. Information obtained from these experiments can be important in understanding the pathogenesis of a neuromuscular disease such as myasthenia gravis. The second chapter utilizes the technique of differential scanning calorimetry to investigate the influence of the receptor microenvironment on the thermostability of the membrane-bound AcChR from Torpedo californica electroplax. In addition, the effect of various ligands and membrane perturbants on the thermal properties of the AcChR is presented. Chapter 3 presents further work on the characterization of certain physicochemical properties of the purified AcChR in detergent solution including thermal stability and isoelectric point in various detergent solutions. Chapter 4 contains a study of the pattern of AcChR activity during regeneration of free muscle transplants of rat extensor digitorum longus muscle, emphasizing the importance to receptor function of re-establishing correct neuromuscular connections.
