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* The Rolf Luft Center for Diabetes Research, Department of Molecular Medicine, Karolinska Institutet, Karolinska Hospital, S-171 76 Stockholm, Sweden;
Institut für Medizinische Biochemie und Molekularbiologie, Universitätskrankenhaus Eppendorf, Universität Hamburg, 20246 Hamburg, Germany; and
Institut für Pharmakologie und Toxikologie, Albert-Ludwig Universität Freiburg, 79104 Freiburg, Germany
1Correspondence: The Rolf Luft Center for Diabetes Research L3, Department of Molecular Medicine, Karolinska Institutet, Karolinska Hospital, S-171 76 Stockholm, Sweden. E-mail: yang.shaonian{at}enk.ks.se
Inositol hexakisphosphate (InsP6) is a most abundant inositol polyphosphate that changes simultaneously with inositol 1,4,5-trisphosphate in depolarized neurons. However, the role of InsP6 in neuronal signaling is unknown. Mass assay reveals that the basal levels of InsP6 in several brain regions tested are similar. InsP6 mass is significantly elevated in activated brain neurons and lowered by inhibition of neuronal activity. Furthermore, the hippocampus is most sensitive to electrical challenge with regard to percentage accumulation of InsP6. In hippocampal neurons, InsP6 stimulates adenylyl cyclase (AC) without influencing cAMP phosphodiesterases, resulting in activation of protein kinase A (PKA) and thereby selective enhancement of voltage-gated L-type Ca2+ channel activity. This enhancement was abolished by preincubation with PKA and AC inhibitors. These data suggest that InsP6 increases L-type Ca2+ channel activity by facilitating phosphorylation of PKA phosphorylation sites. Thus, in hippocampal neurons, InsP6 serves as an important signal in modulation of voltage-gated L-type Ca2+ channel activity.—Yang, S.-N., Yu, J., Mayr, G. W., Hofmann, F., Larsson, O., Berggren, P.-O. Inositol hexakisphosphate increases L-type Ca2+ channel activity by stimulation of adenylyl cyclase.
Key Words: adenylyl cyclase • calcium channel • hippocampus • inositol polyphosphate • protein kinase A
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