The Calcium Store Sensor, STIM1, Reciprocally Controls Orai and Ca _V 1.2 Channels

Abstract

Calcium signals, pivotal in controlling cell function, can be generated by calcium entry channels activated by plasma membrane depolarization or depletion of internal calcium stores. We reveal a regulatory link between these two channel subtypes mediated by the ubiquitous calcium-sensing STIM proteins. STIM1 activation by store depletion or mutational modification strongly suppresses voltage-operated calcium (CaV1.2) channels while activating store-operated Orai channels. Both actions are mediated by the short STIM-Orai activating region (SOAR) of STIM1. STIM1 interacts with CaV1.2 channels and localizes within discrete endoplasmic reticulum/plasma membrane junctions containing both CaV1.2 and Orai1 channels. Hence, STIM1 interacts with and reciprocally controls two major calcium channels hitherto thought to operate independently. Such coordinated control of the widely expressed CaV1.2 and Orai channels has major implications for Ca2+ signal generation in excitable and nonexcitable 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.…”

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

“…Mammalian TRPC channels are weakly Ca 2þ permeable channels with a long history of association with SOCE, but whether they are truly store-dependent is still being debated Wang et al 2010). The strongest evidence of store-dependent activation comes from charge-swapping experiments suggesting that a di-lysine motif in STIM1 interacts with a conserved di-aspartate domain in TRPC1 and other TRPCs to activate these channels following store depletion (Zeng et al 2008).…”

“…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.…”