Human CNNM2 is not a Mg2+ transporter per se

Abstract

CNNM2 is associated with the regulation of serum Mg concentration, and when mutated, with severe familial hypomagnesemia. The function and cellular localization of CNNM2 and its isomorphs (Iso) remain controversial. The objective of this work was to examine the following: (1) the transcription-responsiveness of CNNM2 to Mg starvation, (2) the cellular localization of Iso1 and Iso2, (3) the ability of Iso1 and Iso2 to transport Mg(2+), and (4) the complex-forming ability and spectra of potential interactors of Iso1 and Iso2. The five main findings are as follows. (1) Mg-starvation induces CNNM2 overexpression that is markedly higher in JVM-13 cells (lymphoblasts) compared with Jurkat cells (T-lymphocytes). (2) Iso1 and Iso2 localize throughout various subcellular compartments in transgenic HEK293 cells overexpressing Iso1 or Iso2. (3) Iso1 and Iso2 do not transport Mg(2+) in an electrogenic or electroneutral mode in transgenic HEK293 cells overexpressing Iso1 or Iso2. (4) Both Iso1 and Iso2 form complexes of a higher molecular order. (5) The spectrum of potential interactors of Iso1 is ten times smaller than that of Iso2. We conclude that sensitivity of CNNM2 expression to extracellular Mg(2+) depletion depends on cell type. Iso1 and Iso2 exhibit a dispersed pattern of cellular distribution; thus, they are not exclusively integral to the cytoplasmic membrane. Iso1 and Iso2 are not Mg(2+) transporters per se. Both isomorphs form protein complexes, and divergent spectra of potential interactors of Iso1 and Iso2 indicate that each isomorph has a distinctive function. CNNM2 is therefore the first ever identified Mg(2+) homeostatic factor without being a Mg(2+) transporter per se.

CrossTalk opposing view: CNNM proteins are not Na+/Mg2+ exchangers but Mg2+ transport regulators playing a central role in transepithelial Mg2+ (re)absorption

“…Third, Kolisek's group could not detect CNNM2‐mediated Mg 2+ influx nor efflux, questioning the ability of CNNMs to transport Mg 2+ (Sponder et al . ). Several important limitations of these experiments have to be considered.…”

“…; Sponder et al . ), although a minor Mg 2+ ‐dependent Na + current was detected in HEK293 cells overexpressing CNNM2 (Stuiver et al . ; Yamazaki et al .…”

Structural Basis of the Oncogenic Interaction of Phosphatase PRL-1 with the Magnesium Transporter CNNM2

“…In contrast, mutations in CNNM4, the closest homolog of CNNM2, are considered the cause of the autosome-recessive cone-rod dystrophy with amelogenesis imperfecta (MIM217080) (28,29). Although it is well recognized that CNNM family members control intracellular magnesium levels, there is a debate about their activity as either efflux (18) or influx (17) transporters or, alternatively, as sensors (23) or homeostatic factors (30) that indirectly regulate transcellular Mg 2ϩ transport. Importantly, recent findings highlight essential roles of the CNNM family, such as regulation of the circadian rhythm (31) and reproduction (32).…”

Physiological and oncogenic roles of the PRL phosphatases

“…Moreover, a mutation in CNNM2 (T568I) was discovered in a patient with dominant hypomagnesemia, which was confirmed in vitro to decrease the CNNM2‐specific magnesium current . It is still undetermined if CNNM2 is able to transport magnesium directly or act as an intracellular ion sensor . The subcellular localization of CNNM3 was similarly shown to be at the plasma membrane, but a fainter signal was also observed intracellularly .…”