1. Department of Biological Sciences, Columbia University, New York, New York 10027, USA
2. These authors contributed equally to this work

Correspondence to: Jian Yang Correspondence and requests for materials should be addressed to J.Y. (e-mail: Email: jy160@columbia.edu).

Abstract

Voltage-gated calcium channels (VGCCs) conduct calcium into cells after membrane depolarization and are vital for diverse biological events¹. They are regulated by various signalling pathways, which has profound functional consequences^{1, 2}. The activity of VGCCs decreases with time in whole-cell and inside-out patch-clamp recordings³. This rundown reflects persistent intrinsic modulation of VGCCs in intact cells. Although several mechanisms have been reported to contribute to rundown of L-type channels^{3, 4, 5, 6}, the mechanism of rundown of other types of VGCC is poorly understood. Here we show that phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P₂), an essential regulator of ion channels and transporters^{7, 8, 9, 10, 11, 12, 13, 14}, is crucial for maintaining the activity of P/Q- and N-type channels. Activation of membrane receptors that stimulate hydrolysis of PtdIns(4,5)P₂ causes channel inhibition in oocytes and neurons. PtdIns(4,5)P₂ also inhibits P/Q-type channels by altering the voltage dependence of channel activation and making the channels more difficult to open. This inhibition is alleviated by phosphorylation by protein kinase A. The dual actions of PtdIns(4,5)P₂ and the crosstalk between PtdIns(4,5)P₂ and protein kinase A set up a dynamic mechanism through which the activity of VGCCs can be finely tuned by various neurotransmitters, hormones and trophic factors.