SOCE and STIM1 signaling in the heart: Timing and location matter

Abstract

Store operated Ca²⁺ entry (SOCE) is an ancient and ubiquitous Ca²⁺ signaling pathway discovered decades ago, but the function of SOCE in human physiology is only now being revealed. The relevance of this pathway to striated muscle was solidified with the description of skeletal myopathies that result from mutations in STIM1 and Orai1, the two SOCE components. Here, we consider the evidence for STIM1 and SOCE in cardiac muscle and the sinoatrial node. We highlight recent studies revealing a role for STIM1 in cardiac growth in response to developmental and pathologic cues. We also review the role of STIM1 in the regulation of SOCE and Ca²⁺ store refilling in a non-Orai dependent manner. Finally, we discuss the importance of this pathway in ventricular cardiomyocytes where SOCE contribute to developmental growth and in pacemaker cells where SOCE likely has a fundamental to generating the cardiac rhythm.

Keywords: Cardiac muscle; Store-operated calcium channels; Store-operated calcium entry; Stromal interaction molecule 1 (STIM1).

Figure 1:

Schematic for STIM1 in cardiomyocytes. A) STIM1 localizes in the SR where it makes connections to different target molecules. B) Canonical SOCE is influenced by the set of spliced variants of STIM proteins. STIM1-L is constitutively associated with Orai1 channels whereas STIM1-S is recruited to sarcolemma in response to Ca²⁺ store depletion. C) STIM1 was proposed to inhibit cav1.2 in smooth muscle and neurons. Here STIM1 is localized on the cell surface to block voltage activated Ca²⁺ entry. D) STIM1 spliced forms can bind to and activate transient receptor potential (TRPC) channels. E) EB1 proteins are binding partners with STIM1 and forge a link between STIM1 in the SR membrane to the microtubules network.

Figure 2:

Identification of novel STIM1 interacting partners. A) STIM1 domains include the ER luminal domains that contain the SAM and EF hands. These domains function as the Ca²⁺ sensor of SR store content. Cytosolic oriented STIM1 contains regions critical for Orai channel gained within the CC domains. Additional domains include the ERM and lysine rich regions. B) Design of a screen for STIM1 interacting partners. Biotinylated STIM1 is adheres to a neurtravadin coated plate. Bindings partners from phage display or lysates can be layered into the wells. Detection of the interaction is detected with an ELIZA assay using relevant antibodies. C) Phospholamban was detected as STIM1 partner using the screen. Proposed mechanism is shown for how STIM1 regulates PLN/SERCA2a function in cardiomyocytes.

Figure 3:

STIM1 and SOCE regulate sinus node function. A) STIM1-LacZ is detected in the thick section of the heart of an adult mouse. B-galactosidase staining reveals STIM1 enrichment in the SAN, coronary arteries and aortic valve structures. B) Model of action potential of the SAN. Relevant currents that coordinate diastolic depolarization (green) and repolarization (red) are indicated. Speculative role of SOCE in the SAN AP is shown. C) Model for the role of STIM1 in the SAN to regulate Orai1 directly and cav1.2 and NCX1 indirectly. Because SOC current is an inward Ca²⁺ current activated by depletion of SR Ca²⁺ stores it severs to link the membrane and Ca²⁺ clocks to coordinate diastolic depolarization.