TRP-Na+/Ca2+ Exchanger Coupling

Abstract

Na(+)/Ca(2+) exchangers (NCXs) have traditionally been viewed principally as a means of Ca(2+) removal from non-excitable cells. However there has recently been increasing interest in the operation of NCXs in reverse mode acting as a means of eliciting Ca(2+) entry into these cells. Reverse mode exchange requires a significant change in the normal resting transmembrane ion gradients and membrane potential, which has been suggested to occur principally via the coupling of NCXs to localised Na(+) entry through non-selective cation channels such as canonical transient receptor potential (TRPC) channels. Here we review evidence for functional or physical coupling of NCXs to non-selective cation channels, and how this affects NCX activity in non-excitable cells. In particular we focus on the potential role of nanojunctions, where the close apposition of plasma and intracellular membranes may help create the conditions needed for the generation of localised rises in Na(+) concentration that would be required to trigger reverse mode exchange.

H+ and Pi Byproducts of Glycosylation Affect Ca2+ Homeostasis and Are Retrieved from the Golgi Complex by Homologs of TMEM165 and XPR1

“…Such antagonism was expected, because H + /Ca 2+ exchangers are generally thought to operate in “reverse mode” in conditions where the luminal H + concentration is low and the Ca 2+ concentration is high, potentially causing futile cycles between Vcx1 and Pmc1 in the absence of Vph1. Reverse-mode operation of Na + /Ca 2+ exchangers is well established ( Harper and Sage 2016 ). That reverse-mode operation of Vcx1 (observed in vph1∆ mutants with FK506) did not occur in the absence of FK506 suggests that calcineurin regulates both forward and reverse modes of Vcx1 through a process that is independent of the V-ATPase.…”

A Calcium/Cation Exchanger Participates in the Programmed Cell Death and in vitro Virulence of Entamoeba histolytica

“…Similarly, the overexpression of NCX proteins enhances the heart rate mediated by beta-adrenergic (Kaese et al, 2017 ), and the relaxation of gastric fundus (Fujimoto et al, 2016 ). We are hypothesizing that, as calcium/cation exchangers can reverse the ions transport under certain conditions (Harper and Sage, 2016 ), the different stimuli that are involved in the E. histolytica virulence could increase the Ca 2+ influx via EhCCX, extending the period of high Ca 2+ levels in cytoplasm, maintaining the response to the signal. Such mechanism of Ca 2+ influx via NCX has also been proposed to explain the enhanced contraction displayed by the urinary bladder smooth muscles of transgenic mice overexpressing NCX1.3 (Yamamura et al, 2013 ).…”

“…PMCAs have high Ca 2+ affinity, but low turnover rates, while exchangers have a lower Ca 2+ affinity, but higher turnover rates (Blaustein and Lederer, 1999 ). Consequently, PMCAs are involved in the maintenance of the resting cytoplasmic concentration of Ca 2+ , whereas exchangers are important in the restoration of cytoplasmic concentration of Ca 2+ after it has been elevated during signaling (Harper and Sage, 2016 ). Interestingly, exchangers also participate in the entry of Ca 2+ to cytoplasm, since they can reverse its transport in response to changes in the concentration of the transported ions and membrane potential (Harper and Sage, 2016 ).…”

“…Consequently, PMCAs are involved in the maintenance of the resting cytoplasmic concentration of Ca 2+ , whereas exchangers are important in the restoration of cytoplasmic concentration of Ca 2+ after it has been elevated during signaling (Harper and Sage, 2016 ). Interestingly, exchangers also participate in the entry of Ca 2+ to cytoplasm, since they can reverse its transport in response to changes in the concentration of the transported ions and membrane potential (Harper and Sage, 2016 ). The superfamily of calcium exchangers comprises five branches (Lytton, 2007 ; Emery et al, 2012 ): (i) H + / Ca 2+ exchangers (CAX), mainly found in plants; (ii) bacteria exchangers (YRGB); (iii) Na + /Ca 2+ exchangers (NCX or SLC8); (iv) Na + /Ca 2+ + K + exchangers (NCKX or SLC24); and (v) Ca 2+ /cation exchangers (CCX), which contains one mammalian member, the Na + /Ca 2+ or Li + exchanger (NCLX) that is also named as NCKX6.…”

TRPC Channels in Cardiac Plasticity

“…TRPC3 reportedly interacts with NCX1 in cardiomyocytes [40,66,67]. Functional coupling between TRPC and NCX has also been recognized in other cellular systems in which Na + entry mediated by TRPC3 drives a reverse mode of NCX that evokes further Ca 2+ entry into the cell [68]. However, the interaction between TRPC3 and NCX1 plays an important role in the conduction system, rather than structural remodeling.…”