Expression of the e-subunit gene of the acetylcholine receptor (AChR) by myonuclei located at the neuromuscular junction is precisely regulated during development. A key role in this regulation is played by the synaptic portion of the basal lamina, a structure that is also known to contain agrin, a component responsible for the formation of postsynaptic specializations. We
The expression of acetylcholine receptors (AChR) at neuromuscular synapses in skeletal muscle is regulated by innervation. Recent evidence suggests that the neurotrophic factors involved in the expression of AChR subunit genes may be related to the prion protein (PrPc), a protein of unknown function expressed primarily in neurons which, in its modified form, PrPSc, is thought to have a role in the pathogenesis of transmissible spongiform encephalopathies. We have tested for an involvement of PrPc in the neurotrophic regulation of synaptic AChRs in muscle by comparing the contents of AChR epsilon- and gamma-subunit mRNAs by Northern blot analysis and by in situ hybridization in mice with normal and with deleted PrP genes. At the protein level, AChR expression was assessed electrophysiologically. No difference was found between muscles from the two types of animals, suggesting that the neural regulation of AChR subunit expression in skeletal muscle can be mediated by factors that are not derived from the PrP gene.
Purpose Pulmonary vein isolation (PVI) by catheter ablation has reduced efficacy for the treatment of persistent atrial fibrillation (persAF), as compared to paroxysmal atrial fibrillation (paroxAF). We investigated whether the selection of persAF patients for PVI who Bstep back^to the paroxysmal stage on amiodarone offers a success rate comparable to that of patients with paroxAF. Methods Sixty-two consecutive persAF patients and 62 matched control patients with paroxAF were included. Persistent patients were started on amiodarone and cardioverted to sinus rhythm (SR). PVI was performed after 3 months in those who Bstepped back^and had sustained SR and in all paroxAF patients. Results Five of the 62 (8%) study patients returned to persAF after cardioversion; despite amiodarone, they did not undergo PVI. The rest received PVI and was followed for a mean of 31 ± 14 months. Redo procedures were performed in 44% and 29% in the persAF and paroxAF group (p = 0.093), respectively. The recurrence rate after multiple procedures without antiarrhythmic drugs was similar among the persAF and paroxAF patients (11% and 7%) at 6 months (p = 0.510), but increased in the persAF group at 1 year (21% and 9%, p = 0.065) and exceeded that of the paroxAF group at the end of the follow-up (26% and 12%, p = 0.046). Kaplan-Meier survival analysis showed shorter time to recurrence in the persAF group (p = 0.045). Conclusion PersAF patients who Bstep back^to the paroxysmal stage on amiodarone can expect long-term success of a PVI-only strategy in more than 70% of the time. However, late recurrences are more common compared to paroxAF.
To test the hypothesis that synaptic basal lamina can induce synapse-specific expression of acetylcholine receptor (AChR) genes, we examined the levels mRNA for the alpha- and epsilon-subunits of the AChR in regenerating rat soleus muscles up to 17 days of regeneration. Following destruction of all muscle fibres and their nuclei by exposure to venom of the Australian tiger snake, new fibres regenerated within the original basal lamina sheaths. Northern blots showed that original mRNA was lost during degeneration. Early in regeneration, both alpha- and epsilon-subunit mRNAs were present throughout the muscle fibres but in situ hybridization showed them to be concentrated primarily at original synaptic sites, even when the nerve was absent during regeneration. A similar concentration was seen in denervated regenerating muscles kept active by electrical stimulation and in muscles frozen 41–44 hours after venom injection to destroy all cells in the synaptic region of the muscle. Acetylcholine-gated ion channels with properties similar to those at normal neuromuscular junctions were concentrated at original synaptic sites on denervated stimulated muscles. Taken together, these findings provide strong evidence that factors that induce the synapse-specific expression of AChR genes are stably bound to synaptic basal lamina.
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