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