Phosphorylation and Other Conundrums of Na/Ca Exchanger, NCX1

Abstract

The Na+/Ca2+ exchanger (NCX) is an important Ca2+ transport mechanism in virtually all cells in the body. There are three genes that control the expression of NCX in mammals. There are at least 16 alternatively spliced isoforms of NCX1 that target muscle and nerve and other tissues. Here we briefly discuss three remarkable regulatory issues or "conundrums" that involve the most prevalently expressed gene, NCX1. (1) How is NCX1 regulated by phosphorylation? We suggest that the macromolecular complex of NCX1 plays a critical role in the regulation of NCX. The role of the macromolecular complex and evidence supporting its existence and functional importance is presented. (2) Can there be transport block of a single "mode" of NCX1 transport by drugs or therapeutic agents? The simple answer is "no." A brief explanation is provided. (3) How can NCX1 knockout mice live? The answer is "by other compensatory regulatory mechanisms." These conundrums highlight important features in NCX1 and lay the foundation for new experiments to elucidate function and regulation of NCX1 and provide a context for investigations that seek to understand novel therapeutic agents.

Reversed Na+/Ca2+Exchange Contributes to Ca2+Influx and Respiratory Burst in Microglia

“…48 and present study), and the most highly expressed, Slc8a1/NCX1, is an important Ca 2+ transporter in most cells (reviewed in ref. 61). Although we did not detect a change in their expression after inducing phagocytosis for one hour; pathological conditions, other stimuli and those acting over longer periods might affect exchanger expression.…”

Cell Calcium Extrusion Systems and their Role in Epileptogenesis~!2009-05-14~!2010-01-06~!2010-04-21~!

“…Intracellular loop removal by means ofchymotrypsin treatment eliminates NCX inhibition mechanisms, supporting the fact that these mechanisms are indeed found in this region [60]. Other protein-regulating factors include pH, phosphatidylinositol 4,5-bisphosphate (PIP 2 ), ATP, phosphorylation [71]; as well as the exchanger inhibitor peptide (XIP), which completely inhibits activity when interacting with the N-terminal segment of the large intracellular loop [69]. There are a number of proteins that associate with the NCX1 in the intracellular loop that regulate exchanger transport function, such as protein kinases A (PKA) and C (PKC) [72][73][74].…”

The Na⁺/Ca²⁺ Exchanger 1 (NCX1) Variant 3 as the Major Extrusion System in Renal Distal Tubular Transcellular Ca²⁺-Transport

“…Interestingly, the present results demonstrated no effect of PKC signaling on NCX1.3 activity when activated using TPA, which is in contrast to Hwang et al [37] . However, phosphorylation of NCX remains controversial and seems largely dependent on specific circumstances [21,40] . Presumably, NCX1 is part of a macromolecular complex, containing kinases and phosphatases, which might differ among cell lines, tissues and different circumstances.…”