Serine-1321-independent regulation of the mu 1 adult skeletal muscle Na+ channel by protein kinase C

The adult skeletal muscle Na+ channel mu 1 possesses a highly conserved segment between subunit domains III and IV containing a consensus protein kinase C (PKC) phosphorylation site that, in the neuronal isoform, acts as a master control for ''convergent'' regulation by PKC and cAMP-dependent protein kinase. It lacks an approximate to 200-aa segment between domains I and II thought to modulate channel gating. We here demonstrate that mu 1 is regulated by PKC (but not cAMP-dependent protein kinase) in a manner distinct from that observed for the neuronal isoforms, suggesting that under the same conditions muscle excitation could be uncoupled from motor neuron input. Maximal phosphorylation by PKC, in the presence of phosphatase inhibitors, reduced peak Na+ currents by approximate to 90% by decreasing the maximal conductance, caused a -15 mV shift in the midpoint of steady-state inactivation, and caused a slight speeding of inactivation. Surprisingly, these effects were not affected by mutation of the conserved serine (serine-1321) in the interdomain Ill-IV loop. The pattern of current suppression and gating modification by PKC resembles the response of muscle Na+ channels to inhibitory factors present in the serum and cerebrospinal fluid of patients with Guillain-Barre syndrome, multiplesclerosis, and idiopathic demyelinating polyradiculoneuritis.