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