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Dual regulation of voltage-gated calcium channels by PtdIns(4,5)P2


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 consequences1,2. 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 channels3,4,5,6, 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 transporters7,8,9,10,11,12,13,14, 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.

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Figure 1: Stabilization of P/Q-type Ca2+ channel activity by PtdIns(4,5)P2 (PIP2).
Figure 2: Voltage-dependent inhibition of P/Q-type Ca2+ channels by PtdIns(4,5)P2 (PIP2).
Figure 3: Crosstalk between phosphorylation by PKA and PtdIns(4,5)P2 (PIP2).
Figure 4: Model of modulation of P/Q-type Ca2+ channels by PtdIns(4,5)P2 and PKA.
Figure 5: Regulation of P/Q- and N-type Ca2+ channels through receptor-mediated hydrolysis of PtdIns(4,5)P2.


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We thank S. Siegelbaum for comments on the manuscript; Y. Mori for Cav2.1 cDNA; E. Perez-Reyes for β4 cDNA; T. Tanabe for α2δ cDNA; D. J. Julius for p75 and TrkA (wild-type and mutant) cDNAs. This work was supported by a grant to J.Y. from the National Heart, Lung, and Blood Institute. J.Y. is a recipient of the McKnight Scholar Award and the Scholar Research Programme of the EJLB Foundation.

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Correspondence to Jian Yang.

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Wu, L., Bauer, C., Zhen, Xg. et al. Dual regulation of voltage-gated calcium channels by PtdIns(4,5)P2. Nature 419, 947–952 (2002).

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