Towards Understanding the Role of the Na+-Ca2+ Exchanger Isoform 3

Abstract

The Na²⁺-Ca²⁺ exchanger (NCX) is critical for Ca²⁺ homeostasis throughout the body. Of the three isoforms in the NCX family, NCX1 has been extensively studied, providing a good basis for understanding the molecular aspects of the NCX family, including structural resemblances, stoichiometry, and mechanism of exchange. However, the tissue expression of the third isoform of the family, NCX3, together with its proposed involvement in the Ca²⁺ fluxes of the endoplasmic reticulum and the mitochondria suggests a distinctive role for this isoform. Investigations of the exchanger revealed the involvement of NCX3 in diverse processes such as bone formation, TNF-α production, slow-twitch muscle contraction, and long-term potentiation in the hippocampus. Furthermore, the study of its posttranslational modification, its cleavage by the Ca²⁺-sensitive protease, calpain, and its upregulation in numerous stress conditions linked NCX3 to the aberrant Ca²⁺ influx seen during neuronal excitotoxicity in Alzheimer's disease, brain stroke, and neuronal injuries. Hence, beyond its role in calcium homeostasis, NCX3 plays an important role in stress conditions, neuronal excitotoxicity, and metabolism and is thereby a key element in many cell types. The present review aims to survey the knowledge on NCX3, focusing on the recent discoveries on its functional and structural properties, and discusses the implications of NCX3 in both physiological and pathological conditions.

Structure-based dynamic arrays in regulatory domains of sodium-calcium exchanger (NCX) isoforms

“…This is in line with the prolonged Ca 2+ transients and action potential durations in muscles compared with neurons 4, 5, 26 . These hallmark features, assigned to Ca 2+ interactions with CBD1 and CBD2, strictly correlate with characteristic regulatory modes ascribed to matching (full-size) NCX variants 4, 7, 9, 11, 13, 25, 26 . The equilibrium and kinetic parameters measured in isolated NCX1-CBD12-ACDEF preparations 25 were successfully applied to computer-aided dynamic modeling of allosteric activation of the cardiac NCX1 (ACDEF) during the action and resting potentials, thereby providing indispensable information on the dynamic contributions of NCX in handling the Ca 2+ -dependent Ca 2+ -release from the sarcoplasmic reticulum, the Ca 2+ -spark appearance, and duration within local sub-cellular compartments and the fine-tuning of excitation-contraction coupling in cardiomyocytes 35 .…”

“…Functional contributions of NCX2 and NCX3 variants to physiological and pathological settings have been documented 13, 34 , while underscoring the importance of tissue-specific expression and regulatory diversities exhibited by these isoforms and splice variants 3, 4, 6, 9, 11 . The goal of the present work was to determine the structure-dynamic basis underlying the previously reported regulatory diversities in an isolated CBD12 model and full-size NCX variants in order to formulate the principal mechanism underlying the regulatory diversity in NCX proteins.…”

“…1B). NCX3 is predominantly expressed in the brain and skeletal muscle, but it can also be found in osseous tissue and the immune system 8, 10, 11, 13 . Alternative splicing of NCX3 results in at least 5 splice variants and involves the expression of either exon A or exon B (mutually exclusive exons) in the presence or absence of an additional exon C (Fig.…”

“…Alternative splicing of NCX3 results in at least 5 splice variants and involves the expression of either exon A or exon B (mutually exclusive exons) in the presence or absence of an additional exon C (Fig. 1C) 8, 10, 11, 13 . Exon-A-containing NCX3 splice variants are mainly expressed in skeletal muscle, whereas exon-B-containing NCX3 splice variants are mainly expressed in the brain (Fig.…”

Стан Електролітного Балансу Крові У Пацієнтів Із Хронічною Хворобою Нирок Vd Стадії, Які Лікуються Програмним Гемодіалізом

“…Обмін електролітів є тісно взаємопов'язаним, оскільки їх нормальне співвідношення в клітинному та позаклітинному просторах забезпечує гомеостаз організму [2]. Прогресування хронічної хвороби нирок (ХХН) характеризується порушенням метаболізму електролітів крові в двох формах -гіперелектролітемії або гіпоелектролітемії [3,4]. Часто ХХН супроводжується вторинним гіперпаратиреоїдитом (ВГПТ) із підвищенням секреції паратгормону (ПТГ) [5], що сприяє порушенню мінерального обміну [6].…”