The CRAC Channel Activator STIM1 Binds and Inhibits L-Type Voltage-Gated Calcium Channels

Chan Young Park,^1,2 Aleksandr Shcheglovitov,¹ Ricardo Dolmetsch^1,*

Abstract: Voltage- and store-operated calcium (Ca²⁺) channels are the major routes of Ca²⁺ entry in mammalian cells, but little is known about how cells coordinate the activity of these channels to generate coherent calcium signals. We found that STIM1 (stromal interaction molecule 1), the main activator of store-operated Ca²⁺ channels, directly suppresses depolarization-induced opening of the voltage-gated Ca²⁺ channel Ca_V1.2. STIM1 binds to the C terminus of Ca_V1.2 through its Ca²⁺ release–activated Ca²⁺ activation domain, acutely inhibits gating, and causes long-term internalization of the channel from the membrane. This establishes a previously unknown function for STIM1 and provides a molecular mechanism to explain the reciprocal regulation of these two channels in cells.

¹ Department of Neurobiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
² School of Nano-Biotechnology and Chemical Engineering, UNIST, Banyeon-ri 100, Ulsan 689-798, Republic of Korea.

^* To whom correspondence should be addressed. E-mail: ricardo.dolmetsch{at}stanford.edu

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