The electrochemical driving forces across the plasma membrane both in excitable and non-excitable mammalian cells are finely regulated by different ion channels, pumps, and exchangers that are essential for a wide range of biological processes. The modulation between sodium (Na+), calcium (Ca2+), and intracellular downstream pathways is tightly linked through several mechanisms that generate spatiotemporal ion waves. Transient receptors potential melastatin 8 (TRPM8) channels and Store-operated Ca2+ entry (SOCE) are important players related to Na+ and Ca2+ signaling. TRPM8 channels are non-selective ion-permeable channels exhibiting multi-gating mechanisms, being activated by innocuous cool to cold temperatures. The opening of these channels triggers Na+ and Ca2+ influx, while the SOCE mediated by ORAI1-3 channels is 1000-fold more selective for ions Ca2+ than Na+ ions. This feature makes the TRPM8 and SOCE relevant targets that integrate Na+ and Ca2+ signaling. Although clear evidence of interaction between TRPM8 and SOCE modulating Na+ and Ca2+ signaling remain not elusive, this review highlights the hypothesis that TRPM8 could be a crosstalk channel that links Na+ and Ca2+ signaling. Recent evidence indicated that this link can be mainly mediated by the modulation of SOCE and the plasmalemma exchangers, Na+/Ca2+ (NCX1-3), or via K+-dependent Na+/ Ca2+ exchangers (NCKX1-6). Additionally, TRPM8 can interact with SOCE by alterations on GPCR Gαq-subunit, cytosolic Ca2+ concentration, and PIP2 levels. Therefore, providing a novel insight for further understanding of the structure-function relationships of these two cellular signaling pathways during the ionic influx and efflux is crucial. This review overviews the crosstalk between Na+ and Ca2+ signaling in different cell types, highlighting the available evidence of the potential role of TRPM8 and SOCE in Na+/Ca2+ pathways.
Ca2+ and Na+ signaling, TRPM8 channels, SOCE, ORAI channels, Channelopathies