According to the International Association for the Study of Pain (IASP) pain is characterized as an “unpleasant sensory and emotional experience associated with actual or potential tissue damage”. The TRP super-family, compressing up to 28 isoforms in mammals, mediates a myriad of physiological and pathophysiological processes, pain among them. TRP channel might be constituted by similar or different TRP subunits, which will result in the formation of homomeric or heteromeric channels with distinct properties and functions. In this review we will discuss about the function of TRPs in pain, focusing on TRP channles that participate in the transduction of noxious sensation, especially TRPV1 and TRPA1, their expression in nociceptors and their sensitivity to a large number of physical and chemical stimuli.

Store-operated Ca2+ entry (SOCE) is an ubiquitous mechanism for Ca2+ entry in eukaryotic cells. This route for Ca2+ influx is regulated by the filling state of the intracellular Ca2+ stores communicated to the plasma membrane channels by the proteins of the Stromal Interaction Molecule (STIM) family, STIM1, and STIM2. Store-dependent, STIM1-modulated, channels include the Ca2+ release-activated Ca2+ channels, comprised of subunits of Orai proteins, as well as the store-operated Ca2+ (SOC) channels, involving Orai1, and members of the canonical transient receptor potential family of proteins. Recent studies have revealed the expression of splice variants of STIM1, STIM2, and Orai1 in different cell types. While certain variants are ubiquitously expressed, others, such as STIM1L, show a more restricted expression. The splice variants for STIM and Orai1 proteins exhibit significant functional differences and reveal that alternative splicing enhance the functional diversity of STIM1, STIM2, and Orai1 genes to modulate the dynamics of Ca2+ signals.

There is growing evidence that ion channels are critically involved in cancer cell invasiveness and metastasis. However, the molecular mechanisms of ion signaling promoting cancer behavior are poorly understood and the complexity of the underlying remodeling during metastasis remains to be explored. Here, using a variety of in vitro and in vivo techniques, we show that metastatic prostate cancer cells acquire a specific Na + /Ca 2+ signature required for persistent invasion. We identify the Na + leak channel, NALCN, which is overexpressed in metastatic prostate cancer, as a major initiator and regulator of Ca 2+ oscillations required for invadopodia formation. Indeed, NALCN-mediated Na + influx into cancer cells maintains intracellular Ca 2+ oscillations via a specific chain of ion transport proteins including plasmalemmal and mitochondrial Na + /Ca 2+ exchangers, SERCA and store-operated channels. This signaling cascade promotes activity of the NACLN-colocalized proto-oncogene Src kinase, actin remodeling and secretion of proteolytic enzymes, thus increasing cancer cell invasive potential and metastatic lesions in vivo. Overall, our findings provide new insights into an ion signaling pathway specific for metastatic cells where NALCN acts as persistent invasion controller.

Cytosolic Ca2+ oscillations provide signaling input to several effector systems of the cell. These include neuronal development, migration and networking. Although similar signaling events are hijacked by highly aggressive cancer cells, the mechanism(s) driving the ′neuron-like′ remodeling of the intracellular ionic signature upon cancer progression remains largely elusive. Here, we identify the ′neuronal′ Na+ leak channel, NALCN, in metastatic cells at the hot spots of invadopodia formation and Ca2+ event initiation. Mechanistically, NALCN-mediated Na+ influx associates functionally with plasmalemmal and mitochondrial Na+/Ca2+ exchangers (NCX and NCLX), reactive oxygen species (ROS) and store-operated Ca2+ entry (SOCE)/endoplasmic reticulum Ca2+ uptake (SERCA) systems to generate intracellular Ca2+ oscillations. In turn, the oscillatory activity promotes Src-regulated actin remodeling, Ca2+-dependent secretion of proteolytic enzymes and leads to invadopodogenesis, resulting in tumor progression and metastatic lesions in vivo . Thus, we have uncovered malignant assignment of NALCN giving rise to a critical intracellular Na+/Ca2+ signaling axis.