Inositol hexakisphosphate increases L-type Ca2+ channel activity by stimulation of adenylyl cyclase

Inositol hexakisphosphate (InsP(6))is a most abundant inositol polyphosphat e that changes simultaneously with inositol 1,4,5- trisphosphate in depolar ized 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 h ippocampus is most sensitive to electrical challenge with regard to percent age accumulation of InsP6. In hippocampal neurons, InsP6 stimulates adenyly l cyclase (AC) without influencing cAMP phosphodiesterases, resulting in ac tivation of protein kinase A (PKA) and thereby selective enhancement of vol tage-gated L- type Ca2+ channel activity. This enhancement was abolished by preincubation with PKA and AC inhibitors. These data suggest that InsP6 in creases L- type Ca2+ channel activity by facilitating phosphorylation of PK A phosphorylation sites. Thus, in hippocampal neurons, InsP6 serves as an i mportant signal in modulation of voltage-gated L-type Ca2+ channel activity .