The Complex Role of Store Operated Calcium Entry Pathways and Related Proteins in the Function of Cardiac, Skeletal and Vascular Smooth Muscle Cells

Abstract

Cardiac, skeletal, and smooth muscle cells shared the common feature of contraction in response to different stimuli. Agonist-induced muscle's contraction is triggered by a cytosolic free Ca²⁺ concentration increase due to a rapid Ca²⁺ release from intracellular stores and a transmembrane Ca²⁺ influx, mainly through L-type Ca²⁺ channels. Compelling evidences have demonstrated that Ca²⁺ might also enter through other cationic channels such as Store-Operated Ca²⁺ Channels (SOCCs), involved in several physiological functions and pathological conditions. The opening of SOCCs is regulated by the filling state of the intracellular Ca²⁺ store, the sarcoplasmic reticulum, which communicates to the plasma membrane channels through the Stromal Interaction Molecule 1/2 (STIM1/2) protein. In muscle cells, SOCCs can be mainly non-selective cation channels formed by Orai1 and other members of the Transient Receptor Potential-Canonical (TRPC) channels family, as well as highly selective Ca²⁺ Release-Activated Ca²⁺ (CRAC) channels, formed exclusively by subunits of Orai proteins likely organized in macromolecular complexes. This review summarizes the current knowledge of the complex role of Store Operated Calcium Entry (SOCE) pathways and related proteins in the function of cardiac, skeletal, and vascular smooth muscle cells.

Keywords: Ca2+; Orai; STIM; TRPC; cardiomyocyte; skeletal muscle; vascular smooth muscle.

Figure 1

A scheme illustrating the standard mechanism and molecular components of SOCE in vascular smooth muscle cells. Store depletion by thapsigargin or vasoactive agonists binding to GPCR, induces Ca²⁺ store depletion, STIM1 organization in puncta and translocation to the plasma membrane, activation of Ca²⁺ entry through Orai1 and/or TRPC-dependent SOCC. A mechanism involving Orai1, TRPC1 and the voltage-sensitive Cav1.2, has also been implicated in Ca²⁺ influx induced by SOCE. Agonists also stimulate store independent Ca²⁺ entry through Orai1/3 activated by AA or LTC4; or through TRPC3/6/7 activated by DAG.

Figure 2

A scheme illustrating the standard mechanism and molecular components of SOCE in skeletal muscle. At the triad junction, the voltage-sensitive Ca_V1.1 and RyR1 interacts physically. STIM1 and STIM1L are in close proximity or in complex with Orai1 even before store depletion. This pre-localization of STIM1/1L with Orai1 likely facilitates the fast-activation kinetics of SOCE. A similar mechanism involving TRPC channels and STIM1 has also been implicated in Ca²⁺ influx mechanisms. STIM1 interacts with STIM2, which regulates SERCA1-mediated filling of the SR Ca²⁺ store and sustains resting [Ca²⁺] in the cytosol.

Figure 3

A scheme illustrating the standard mechanism and molecular components of SOCE in cardiac muscle. Store depletion involves STIM1/1L interaction with Orai1 which likely recruits Orai3. STIM1/1L colocalizes with key regulators of SOCE such as Orai1, SERCA, phospholamban (PLB), and RyR2. A similar mechanism involving TRPC1/4/5 channels and STIM1 has also been implicated in SOCE. Store independent Ca²⁺ entry through Orai3 activated by AA, or via TRPC3/6 activated by DAG has been described.