Regulation of voltage-dependent sodium channel expression in adrenal chromaffin cells: involvement of multiple calcium signaling pathways.
The density and electrical activity of cell surface voltage-dependent Na(+) channels are key determinants regulating the neuronal plasticity including development, differentiation, and regeneration. Abnormalities of Na(+) channels are associated with various neurological diseases. In this paper, we review the regulatory mechanisms of cell surface Na(+) channel expression mediated by Ca(2+) signaling pathways in cultured bovine adrenal chromaffin cells. Sustained, but not transient, elevation of intracellular Ca(2+) concentration reduced the number of cell surface Na(+) channels. The reduction of Na(+) channels was suppressed by an inhibitor of calpain, a Ca(2+)-dependent protease, and by an inhibitor of protein kinase C (PKC). The activation of conventional PKC-alpha and novel PKC-epsilon reduced cell surface Na(+) channels by the acceleration of internalization of the channels and by the increased degradation of Na(+) channel alpha-subunit mRNA, respectively. On the contrary, the activation of PKC-epsilon increased Na(+) channel beta(1)-subunit mRNA level. The inhibition of calcineurin, a Ca(2+)/calmodulin-dependent protein phosphatase 2B, by immunosuppressants upregulated cell surface Na(+) channels by both stimulating externalization and inhibiting internalization of the channels without changing Na(+) channel alpha- and beta(1)-subunit mRNA levels. Thus, the signal transduction pathways mediated by intracellular Ca(2+) modulate cell surface Na(+) channel expression via multiple Ca(2+)-dependent events, and the changes in the intracellular vesicular trafficking are the important mechanisms in the regulation of Na(+) channel expression.
Kobayashi
Hideyuki
H
Department of Pharmacology, Miyazaki Medical College, Miyazaki 889-1692, Japan. hkobayas@post.miyazaki-med.ac.jp
Shiraishi
Seiji
S
Yanagita
Toshihiko
T
Yokoo
Hiroki
H
Yamamoto
Ryuichi
R
Minami
Shin-Ichi
S
Saitoh
Tomokazu
T
Wada
Akihiko
A
D000311:Adrenal Glands / Q000166:cytology*; D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002154:Calpain / Q000378:metabolism; D002417:Cattle; D019439:Chromaffin Cells / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008954:Models, Biological; D011493:Protein Kinase C / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000378:metabolism*
D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D015222:Sodium Channels; D012964:Sodium; D011493:Protein Kinase C; D019703:Calcineurin; D002154:Calpain; D002118:Calcium