On the Connections between TRPM Channels and SOCE

Plasma membrane protein channels provide a passageway for ions to access the intracellular milieu. Rapid entry of calcium ions into cells is controlled mostly by ion channels, while Ca²⁺-ATPases and Ca²⁺ exchangers ensure that cytosolic Ca²⁺ levels ([Ca²⁺ ]_cyt) are maintained at low (~100 nM) concentrations. Some channels, such as the Ca²⁺-release-activated Ca²⁺ (CRAC) channels and voltagedependent Ca²⁺ channels (CACNAs), are highly Ca²⁺-selective, while others, including the Transient Receptor Potential Melastatin (TRPM) family, have broader selectivity and are mostly permeable to monovalent and divalent cations. Activation of CRAC channels involves the coupling between ORAI1-3 channels with the endoplasmic reticulum (ER) located Ca²⁺ store sensor, Stromal Interaction Molecules 1-2 (STIM1/2), a pathway also termed store-operated Ca²⁺ entry (SOCE). The TRPM family is formed by 8 members (TRPM1-8) permeable to Mg²⁺, Ca²⁺, Zn²⁺ and Na⁺ cations, and is activated by multiple stimuli. Recent studies indicated that SOCE and TRPM structure-function are interlinked in some instances, although the molecular details of this interaction are only emerging. Here we review the role of TRPM and SOCE in Ca²⁺ handling and highlight the available evidence for this interaction.