Arachidonic acid modulation of alpha1H, a cloned human T-type calcium channel.
Arachidonic acid (AA) and the products of its metabolism are central mediators of changes in cellular excitability. We show that the recently cloned and expressed T-type or low-voltage-activated Ca channel, alpha1H, is modulated by external AA. AA (10 microM) causes a slow, time-dependent attenuation of alpha1H current. At a holding potential of -80 mV, 10 microM AA reduces peak inward alpha1H 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 inhibitor nordihydroguaiaretic acid. The epoxygenase inhibitor octadecynoic acid partially antagonized AA attenuation of alpha1H. The epoxygenase metabolite epoxyeicosatrienoic acid (8,9-EET) mimicked the inhibitory effect of AA on alpha1H peak current. A protein kinase C (PKC)-specific inhibitor (peptide fragment 19-36) only partially antagonized the AA-induced reduction of peak alpha1H current and the shift of the steady-state inactivation curve but had no effect on 8,9-EET-induced attenuation of current. In contrast, PKA has no role in the modulation of alpha1H. These results suggest that AA attenuation and shift of alpha1H may be mediated directly by AA. The heterologous expression of T-type Ca channels allows us to study for the first time properties of this important class of ion channel in isolation. There is a significant overlap of the steady-state activation and inactivation curves, which implies a substantial window current. The selective shift of the steady-state inactivation curve by AA reduces peak Ca current and eliminates the window current. We conclude that AA may partly mediate physiological effects such as vasodilatation via the attenuation of T-type Ca channel current and the elimination of a T-type channel steady window current.
Zhang
Y
Y
Department of Physiology, The University of Kentucky College of Medicine, Lexington, Kentucky 40536-0298, USA.
Cribbs
L L
LL
Satin
J
J
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D016718:Arachidonic Acid / Q000494:pharmacology*; D020747:Calcium Channels, T-Type / Q000187:drug effects / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D002460:Cell Line; D003001:Cloning, Molecular; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004553:Electric Conductivity; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology
D020747:Calcium Channels, T-Type; D004791:Enzyme Inhibitors; D016718:Arachidonic Acid; C050715:8,9-epoxyeicosatrienoic acid; D003577:Cytochrome P-450 Enzyme System; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D015126:8,11,14-Eicosatrienoic Acid