Inositol hexakisphosphate increases L‐type Ca ²⁺ channel activity by stimulation of adenylyl cyclase

Inositol hexakisphosphate (InsP 6 ) is a most abundant inositol polyphosphate that changes simultaneously with inositol 1,4,5‐trisphosphate in depolarized neurons. However, the role of InsP 6 in neuronal signaling is unknown. Mass assay reveals that the basal levels of InsP 6 in several brain regions tested are similar. InsP 6 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 InsP 6 . In hippocampal neurons, InsP 6 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 Ca 2+ channel activity. This enhancement was abolished by preincubation with PKA and AC inhibitors. These data suggest that InsP 6 increases L‐type Ca 2+ channel activity by facilitating phosphorylation of PKA phosphorylation sites. Thus, in hippocampal neurons, InsP 6 serves as an important signal in modulation of voltage‐gated L‐type Ca 2+ channel activity.—Yang, S.‐N., Yu, J., Mayr, G. W., Hofmann, F., Larsson, O., Berggren, P.‐O. Inositol hexakisphosphate increases L‐type Ca 2+ channel activity by stimulation of adenylyl cyclase. FASEB J. 15, 1753–1763 (2001)