Zinc-Permeable Ion Channels: Effects on Intracellular Zinc Dynamics and Potential Physiological/Pathophysiological Significance

Abstract

Zinc (Zn2+) is one of the most important trace metals in the body. It is necessary for the normal function of a large number of proteins including enzymes and transcription factors. While extracellular fluid may contain up to micromolar Zn2+, intracellular Zn2+ concentration is generally maintained at a subnanomolar level; this steep gradient across the cell membrane is primarily attributable to Zn2+ extrusion by Zn2+ transporting systems. Interestingly, systematic investigation has revealed that activities, previously believed to be dependent on calcium (Ca2+), may be partially mediated by Zn2+. This is also supported by new findings that some Ca2+-permeable channels such as voltage-dependent calcium channels (VDCCs), N-methyl-D-aspartate receptors (NMDA), and amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors (AMPA-Rs) are also permeable to Zn2+. Thus, the importance of Zn2+ in physiological and pathophysiological processes is now more widely appreciated. In this review, we describe Zn2+-permeable membrane molecules, especially Zn2+-permeable ion channels, in intracellular Zn2+dynamics and Zn2+ mediated physiology/pathophysiology.

Zinc transporters and dysregulated channels in cancers

“…Long before the first mammalian Zn transporter, i.e., ZnT1 was discovered two decades ago, Zn was thought to cross membranes through certain ion channels (52, 53). Because of the similar divalent cationic properties of Ca 2+ and Zn 2+ , some Ca 2 + permeable channels were suspected to be Zn permeable.…”

“…TRP channels have widespread distribution in the human body and play important roles in a wide range of physiological and pathophysiological processes, such as cell proliferation, migration, adhesion, differentiation, apoptosis and necroptosis. Based on patch clamp and fluorescent Zn 2+ imaging data, several members of this family are Zn 2+ -permeable, such as TRPC6, TRPV6, TRPM3, TRPM6/7, TRPML1 and TRPA1 (53). TRPM6 and TRPM7 are two unique TRP channels in that they contain both ion conducting pore and kinase domains (63).…”

Addictive neurons

“…It is common that either the activation of one receptor type may influence another one or they interact [80] . Moreover, a single substance may target multiple receptor and channel types as it could be exemplified by zinc [81] . WIN55,212-2 at 1 µM almost abolishes the 30 µM serotonin evoked inward currents at −100 mV in HEK 293 cells expressing h5-HT 3A receptors [82] .…”

Metal Ions Introduced to Proteins by Supramolecular Ligands

“…They form a variety of compounds with interesting spectroscopic and magnetic properties whose practical applications are the subject of ongoing research [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17]. In the cell, metals are usually found in their complexed form, either as standalone ions or inside specific planar carrier compounds encapsulated by proteins -e.g.…”