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

Abstract

Voltage- and store-operated calcium (Ca(2+)) channels are the major routes of Ca(2+) 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 Ca(2+) channels, directly suppresses depolarization-induced opening of the voltage-gated Ca(2+) channel Ca(V)1.2. STIM1 binds to the C terminus of Ca(V)1.2 through its Ca(2+) release-activated Ca(2+) 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.

STIM2 regulates AMPA receptor trafficking and plasticity at hippocampal synapses

“…Consistent with a function of STIM2 at the synapse, STIM2 is found in approximately half of hippocampal spines 7,8 and presumably operates at contact sites between the ER and the dendritic PM to regulate the neuronal SOCE channel (yet to be identified) 8 the AMPAR 7 , the postsynaptic voltage-gated Ca 2+ channel Cav1.2 5,16 and possibly other effectors.…”

“…In most cell types, release of ER Ca 2+ triggers Store-Operated Ca 2+ entry (SOCE), a form of Ca 2+ influx which is regulated by the ERresident STIM proteins 3 . While SOCE is the predominant Ca 2+ influx pathway in non-excitable cells 4 , the magnitude and relevance of SOCE in neurons remains a topic of debate [5][6][7] . Recent studies, however, reported SOCE responses in dendritic spines 8,9 , small dendritic protrusions at the tip of which terminate most excitatory inputs.…”

Store-Operated Calcium Channels: New Perspectives on Mechanism and Function

“…Ca V Channels STIM1 was recently and unexpectedly discovered to exert reciprocal actions on storeoperated and voltage-gated Ca 2þ (Ca V 1.2) channels (Park et al 2010;Wang et al 2010). STIM1 inhibits Ca V 1.2 channel function in two ways.…”

Mutations in voltage-gated L-type calcium channel: implications in cardiac arrhythmia

“…Functionally, p.P857R mutation, cosegregated with the disease within the pedigree, significantly increased calcium currents and surface membrane expression of the channel as compared with wild type (WT) Ca V 1.2 channel [84]. Interestingly, p.R1906Q locates one amino acid away from α 1C C-terminal STIM1 (stromal-interacting molecule 1, a calcium store sensor) binding domain, which may affect STIM1-mediated Ca V 1.2 channel gating inhibition and channel internalization [86,87]. The identification of these CACNA1C mutations co-segregating with disease indicated that CACNA1C genetic perturbations might underscore autosomal dominant LQT8 in the absence of TS.…”