Disorders of the neuromuscular junction

This chapter looks at how two fundamentally different pathological processes are associated with disease at the neuromuscular junction: acquired disorders in which autoantibodies are directed against nerve or muscle receptor or ion channels; rare inherited conditions in which the defect may be pre- or postsynaptic. The acquired neuromuscular junction disorders are associated with antibodies directed against one of the ion channels. The fact that there are three autoimmune disorders known to affect such a small region may be explained by the neuromuscular junction, unlike the peripheral nerve, not being contained within the blood–nerve barrier, which stops just short of the nerve terminal, and thus being potentially exposed to circulating humoral attack. The inherited disorders may affect presynaptic processes (acetylcholine resynthesis, packaging, or release), acetylcholinesterase binding, or postsynaptic function (acetylcholine receptor numbers or localization). Pathogenic mechanisms are considered in more detail when discussing individual disorders.

Disorders of the neuromuscular junction

Two fundamentally different pathological processes are associated with disease at the neuromuscular junction: (1) acquired disorders in which autoantibodies are directed against nerve or muscle receptor or ion channels; (2) rare inherited conditions in which the defect may be pre- or postsynaptic. Aetiology and epidemiology—the fundamental disorder is loss of functional acetylcholine receptors most frequently as a result of binding of anti-acetylcholine receptor (anti-AChR) antibodies. Incidence is about 10 per million population and prevalence about 8 per 100 000, with a marked female bias in cases aged under 40 years and male preponderance in those over 50 years. Thymomas occur in about 10% of cases....

Molecular cloning and functional expression of a VIP-specific receptor

Three receptors for VIP and pituitary adenylate cyclase-activating peptide (PACAP) have been cloned and characterized: PAC1, with high affinity for PACAP, and VPAC1 and VPAC2 with equally high affinity for VIP and PACAP. The existence of a VIP-specific receptor (VIPs) in guinea pig (GP) teniae coli smooth muscle was previously surmised on the basis of functional studies, and its existence was confirmed by cloning of a partial NH2-terminal sequence. Here we report the cloning of the full-length cDNAs of two receptors, a VPAC2 receptor from GP gastric smooth muscle and VIPs from GP teniae coli smooth muscle. The cDNA sequence of the VIPs encodes a 437-amino acid protein ( Mr 49,560) that possesses 87% similarity to VPAC2 receptors in rat and mouse and differs from the VPAC2 receptor in GP gastric smooth muscle by only two amino-acid residues, F40F41 in lieu of L40L41. In COS-1 cells transfected with the GP teniae coli smooth muscle receptor, only VIP bound with high affinity (IC50 1.4 nM) and stimulated cAMP formation with high potency (EC50 1 nM). In contrast, in COS-1 cells transfected with the GP gastric smooth muscle receptor, both VIP and PACAP bound with equally high affinity (IC50 2.3 nM) and stimulated cAMP with equally high potency (EC50 1.5 nM). We conclude that the receptor cloned from GP teniae coli smooth muscle is a VIPs distinct from VPAC1 and VPAC2 receptors. The ligand specificity in this species is determined by a pair of adjacent phenylalanine residues (L40L41) in the NH2-terminal ligand-binding domain.

Glutamate release in midbrain periaqueductal gray by activation of skeletal muscle receptors and arterial baroreceptors

We have previously reported that both skeletal muscle receptor and arterial baroreceptor afferent inputs activate neurons in the dorsolateral (DL) and lateral regions of the midbrain periaqueductal gray (PAG). In this study, we determined whether the excitatory amino acid glutamate (Glu) is released to mediate the increased activity in these regions. Static contraction of the triceps surae muscle for 4 min was evoked by electrical stimulation of the L7 and S1 ventral roots in cats. Activation of arterial baroreceptor was induced by intravenous injection of phenylephrine. The endogenous release of Glu from the PAG was recovered with the use of a microdialysis probe. Glu concentration was measured by the HPLC method. Muscle contraction increased mean arterial pressure (MAP) from 98 ± 10 to 149 ± 12 mmHg ( P < 0.05) and increased Glu release in the DL and lateral regions of the middle PAG from 0.39 ± 0.10 to 0.73 ± 0.12 μM (87%, P < 0.05) in intact cats. After sinoaortic denervation and vagotomy were performed, contraction increased MAP from 95 ± 12 to 158 ± 15 mmHg, and Glu from 0.34 ± 0.08 to 0.54 ± 0.10 μM (59%, P < 0.05). The increases in arterial pressure and Glu were abolished by muscle paralysis. Phenylephrine increased MAP from 100 ± 13 to 162 ± 22 mmHg and increased Glu from 0.36 ± 0.10 to 0.59 ± 0.18 μM (64%, P < 0.05) in intact animals. Denervation abolished this Glu increase. Summation of the changes in Glu evoked by muscle receptor and arterial baroreceptor afferent inputs was greater than the increase in Glu produced when both reflexes were activated simultaneously in intact state (123% vs. 87%). These data demonstrate that activation of skeletal muscle receptors evokes release of Glu in the DL and lateral regions of the middle PAG, and convergence of afferent inputs from muscle receptors and arterial baroreceptors in these regions inhibits the release of Glu. These results suggest that the PAG is a neural integrating site for the interaction between the exercise pressor reflex and the arterial baroreceptor reflex.