Homer proteins mediate the interaction between STIM1 and Cav1.2 channels

STIM1 is a ubiquitous Ca 2 + sensor of the intracellular, agonist-sensitive, Ca 2 + stores that communicates the filling state of the Ca 2 + compartments to plasma membrane store-operated Ca 2 + (SOC) channels. STIM1 has been presented as a point of convergence between store-operated and voltage-operated Ca 2 + influx, both inducing activation of SOC channels while suppressing Ca v 1.2 channels. Here we report that Homer proteins play a relevant role in the communication between STIM1 and Ca v 1.2 channels. HEK-293 cells transiently expressing Ca v 1.2 channel subunits α 1 , β 2 and α 2 δ–1 exhibited a significant Ca 2 + entry upon treatment with a high concentration of KCl. In Ca v 1.2-expressing cells, treatment with thapsigargin (TG), to induce passive discharge of the intracellular Ca 2 + stores, resulted in Ca 2 + influx that was significantly greater than in cells not expressing Ca v 1.2 channels, a difference that was abolished by nifedipine and diltiazem. Treatment with TG induces co-immunoprecipitation of Homer1 with STIM1 and the Ca v 1.2 α 1 subunit. Impairment of Homer function by introduction of the synthetic PPKKFR peptide into cells, which emulates the proline-rich sequences of the PPXXF motif, or using siRNA Homer1, reduced the association of STIM1 and the Ca v 1.2 α 1 subunit. These findings indicate that Homer is important for the association between both proteins. Finally, treatment with siRNA Homer1 or the PPKKFR peptide enhanced the nifedipine-sensitive component of TG response in Ca v 1.2-expressing cells. Altogether, these findings provide evidence for a new role of Homer1 supporting the regulation of Cav1.2 channels by STIM1.