Abstract
Autoantibody against neuronal nicotinic acetylcholine receptor (nAChR) α3 subunit is implicated in severe autonomic dysfunction in the patients with autoimmune autonomic ganglionopathy (AAG). Although this autoantibody has been revealed to impair fast excitatory synaptic transmission in autonomic ganglia, its precise mechanism remains unknown. Here, we show that antibody-induced reduction of cell-surface α3 subunits result in impairment of nicotine-evoked Ca2+ influx in stably transfected human embryonic kidney cells. These effects of the antibody were remarkably inhibited by interfering with the endocytic machinery at low-temperature. We conclude that reduction of nAChR in autonomic ganglia can be mediated by the endocytosis of α3 subunits, and resulted in autonomic failure in AAG patients.
Highlights
Autoimmune autonomic ganglionopathy (AAG) is an acquired immune-mediated disorder characterized by severe autonomic dysfunction
Autoantibody against neuronal nicotinic acetylcholine receptor 3 subunit is implicated in severe autonomic dysfunction in the patients with autoimmune autonomic ganglionopathy (AAG)
To confirm whether exogenous α3 and 4 subunits formed functional nicotinic acetylcholine receptor (nAChR), we examined nicotine-evoked Ca2+ influx using Fluo-3 AM (Figure 1(c))
Summary
Autoimmune autonomic ganglionopathy (AAG) is an acquired immune-mediated disorder characterized by severe autonomic dysfunction. The clinical manifestations of AAG include orthostatic hypotension, gastroin-. About 50% of patients with AAG have autoantibodies against ganglion-type neuronal nicotinic acetylcholine receptor (ganglionic nAChR) [2]. NAChR containing α3 and 4 subunits mainly mediates fast excitatory synaptic transmission [3,4]. Previous electrophysiological studies have revealed pathogenic roles of anti-α3 subunit autoantibody. Autonomic dysfunction was induced in rabbits immunized with recombinant α3 subunit protein [5] and in mice given anti-α3 subunit antibodies [6]. Vernino et al [7] demonstrated that IgG from the seropositive patients reduced ganglionic nAChR current in human embryonic kidney (HEK) cells. We further examined whether antibody-induced reduction in the protein levels of cell-surface α3 subunits could cause ganglionic nAChR dysfunction in HEK293 cells
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