β2-Adrenergic Regulation of the Neuromuscular Transmission and Its Lipid-Dependent Switch

Abstractβ2-Adrenoceptors (β2-ARs) are the most abundant subtype of adrenergic receptors in skeletal muscles. Their activation via a stabilization of postsynaptic architecture has beneficial effects in certain models of neuromuscular disorders. However, the ability of β2-ARs to regulate neuromuscular tran smission at the presynaptic level is poorly understood. Using electrophysiological recordings and fluorescent FM dyes, we found that β2-AR activation with fenoterol enhanced an involvement of synaptic vesicles in exocytosis and neurotransmitter release during intense activity at the neuromuscular j unctions of mouse diaphragm. This was accompanied by an improvement of contractile responses to phrenic nerve stimulation (but not direct stimulation of the muscle fibers) at moderate-to-high frequencies. β2-ARs mainly reside in lipid microdomains enriched with cholesterol and sphingomyelin. The la tter is hydrolyzed by sphingomyelinases, whose upregulation occurs in many conditions characterized by muscle atrophy and sympathetic nerve hyperactivity. Sphingomyelinase treatment reversed the effects of β2-AR agonist on the neurotransmitter release and synaptic vesicle recruitment to the exocyto sis during intense activity. Inhibition of Gi protein with pertussis toxin completely prevented the sphingomyelinase-mediated inversion in the β2-AR agonist action. Note that lipid raft disrupting enzyme cholesterol oxidase had the same effect on β2-AR agonist-mediated changes in neuro...
Source: Molecular Neurobiology - Category: Neurology Source Type: research