Serine-1321-independent regulation of the mu 1 adult skeletal muscle Na+ channel by protein kinase C.
The adult skeletal muscle Na+ channel mu1 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 approximately 200-aa segment between domains I and II though to modulate channel gating. We here demonstrate that mu1 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 approximately 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 III-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-Barré syndrome, multiple sclerosis, and idiopathic demyelinating polyradiculoneuritis.
Bendahhou
S
S
Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Cummins
T R
TR
Potts
J F
JF
Tong
J
J
Agnew
W S
WS
D000328:Adult; D000470:Alkaloids / Q000494:pharmacology; D000595:Amino Acid Sequence; D001483:Base Sequence; D002460:Cell Line; D016384:Consensus Sequence; D017124:Conserved Sequence; D017931:DNA Primers; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004988:Ethers, Cyclic / Q000494:pharmacology; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology; D046911:Macromolecular Substances; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008969:Molecular Sequence Data; D009103:Multiple Sclerosis / Q000097:blood / Q000134:cerebrospinal fluid; D018482:Muscle, Skeletal / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D009281:Naphthalenes / Q000494:pharmacology; D019319:Okadaic Acid; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D011129:Polyradiculoneuropathy / Q000097:blood / Q000134:cerebrospinal fluid; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D012694:Serine; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology*; D019311:Staurosporine; D014162:Transfection
D000470:Alkaloids; D017931:DNA Primers; D004791:Enzyme Inhibitors; D004988:Ethers, Cyclic; D046911:Macromolecular Substances; D009281:Naphthalenes; D011994:Recombinant Proteins; D015222:Sodium Channels; D019319:Okadaic Acid; D012694:Serine; D011493:Protein Kinase C; D019311:Staurosporine; C058819:calphostin C