Arachidonic acid modulation of alpha 1H, a cloned human T-type calcium channel

Arachidonic acid (AA) and the products of its metabolism are central mediat ors of changes in cellular excitability. We show that the recently cloned a nd expressed T-type or low-voltage-activated Ca channel, alpha 1H, is modul ated by external AA. AA (10 l-IM) causes a slow, time-dependent attenuation of alpha 1H current. At a holding potential of -80 mV, 10 mu M AA reduces peak inward alpha 1H current by 15% in 15 min and 70% in 30 min and shifts the steady-state inactivation curve -25 mV. AA inhibition was not affected by applying the cyclooxygenase inhibitor indomethacin or the lipoxygenase i nhibitor nordihydroguaiaretic acid. The epoxygenase inhibitor octadecynoic acid partially antagonized AA attenuation of alpha 1H. The epoxygenase meta bolite epoxyeicosatrienoic acid (8,9-EET) mimicked the inhibitory effect of AA on alpha 1H peak current. A protein kinase C (PKC)-specific inhibitor ( peptide fragment 19-36) only partially antagonized the AA-induced reduction of peak alpha 1H current and the shift of the steady-state inactivation cu rve but had no effect on 8,9-EET-induced attenuation of current. In contras t, PKA. has no role in the modulation of alpha 1H. These results suggest th at AA attenuation and shift of alpha 1H may be mediated directly by AA. The heterologous expression of T-type Ca channels allows us to study for the f irst time properties of this important class of ion channel in isolation. T here is a significant overlap of the steady-state activation and inactivati on curves, which implies a substantial window current. The selective shift of the steady-state inactivation curve by AA reduces peak Ca current and el iminates the window current. We conclude that AA may partly mediate physiol ogical effects such as vasodilatation via the attenuation of T-type Ca chan nel current and the elimination of a T-type channel steady window current.