The ATP-Releasing Maxi-Cl Channel: Its Identity, Molecular Partners, and Physiological/Pathophysiological Implications

Abstract

The Maxi-Cl phenotype accounts for the majority (app. 60%) of reports on the large-conductance maxi-anion channels (MACs) and has been detected in almost every type of cell, including placenta, endothelium, lymphocyte, cardiac myocyte, neuron, and glial cells, and in cells originating from humans to frogs. A unitary conductance of 300–400 pS, linear current-to-voltage relationship, relatively high anion-to-cation selectivity, bell-shaped voltage dependency, and sensitivity to extracellular gadolinium are biophysical and pharmacological hallmarks of the Maxi-Cl channel. Its identification as a complex with SLCO2A1 as a core pore-forming component and two auxiliary regulatory proteins, annexin A2 and S100A10 (p11), explains the activation mechanism as Tyr23 dephosphorylation at ANXA2 in parallel with calcium binding at S100A10. In the resting state, SLCO2A1 functions as a prostaglandin transporter whereas upon activation it turns to an anion channel. As an efficient pathway for chloride, Maxi-Cl is implicated in a number of physiologically and pathophysiologically important processes, such as cell volume regulation, fluid secretion, apoptosis, and charge transfer. Maxi-Cl is permeable for ATP and other small signaling molecules serving as an electrogenic pathway in cell-to-cell signal transduction. Mutations at the SLCO2A1 gene cause inherited bone and gut pathologies and malignancies, signifying the Maxi-Cl channel as a perspective pharmacological target.

Properties, Structures, and Physiological Roles of Three Types of Anion Channels Molecularly Identified in the 2010’s

“…Electrophysiological properties of these three types of volume-related anion channels were directly studied by observing their channel currents using patch-clamp techniques, and those were described in detail so far in the review articles for VSOR/VRAC ( Strange et al, 1996 ; Nilius et al, 1997 ; Okada, 1997 ), Maxi-Cl ( Sabirov et al, 2016 , 2021 ), and ASOR/PAC ( Okada et al, 2021b ). The pharmacological properties of these three types of volume-related anion channels are different from each other, as recently summarized in our review article ( Okada et al, 2019b ).…”

Placental ion channels: potential target of chemical exposure

“… * In situ hybridization, Northern Blot, RT-PCR were used to measure mRNA levels, * * western blot to detect protein and * * * immunohistochemistry, immunocytochemistry and immunofluorescence as well as cell fractions and vesicles were used to report localization of ion channels. # A complex with solute carrier organic anion transporter family member 2A1 as a core pore-forming component and two auxiliary regulatory proteins, annexin A2 and S100 calcium binding protein A10 [ 115 ]. CaV, voltage-gated calcium channel; CFTR, cystic fibrosis transmembrane conductance regulator (ATP-binding cassette sub-family C, member 7); CLC, chloride channel; Cx, connexin; K 2P , two-pore domain potassium channel; KCa, calcium-activated potassium channel; K ir , inwardly rectifying potassium channel; nAchR, nicotinic acetylcholine receptor; Na V , voltage-gated sodium channel; P2X, purinergic receptor P2X Px, pannexin; Ryr, ryanodine receptor; TRPM, transient receptor potential cation channel subfamily M; TRPP, transient receptor potential cation channel subfamily P; TRPV, transient receptor potential cation channel subfamily V; ZAC, zinc-activated channel.…”

“… * In situ hybridization, Northern Blot, RT-PCR were used to measure mRNA levels, * * western blot to detect protein and * * * immunohistochemistry, immunocytochemistry and immunofluorescence as well as cell fractions and vesicles were used to report localization of ion channels. # A complex with solute carrier organic anion transporter family member 2A1 as a core pore-forming component and two auxiliary regulatory proteins, annexin A2 and S100 calcium binding protein A10 [ 115 ]. …”

“…However, the expression of these chloride channels is increased in placentae of pre-eclamptic (PE) and intra-uterine growth retardation pregnancies (IUGR), but it remains to be studied whether they contribute to pathological processes of these conditions [ 65 , 90 ]. Maxi-chloride channel is a complex with solute carrier organic anion transporter family member 2A1 (SLCO2A1) as pore-forming component and two auxiliary regulatory proteins, annexin 2 and S100 calcium binding protein A10 (S100A10) [ 115 ] Maxi-chloride channel has been shown to be regulated by arachidonic acid, fatty acids and steroid hormones [ 120 ]. In addition to chloride, the maxi-chloride channel is permeable to amino acids and it may have a role in placental volume regulation [ 121 ].…”

Update on Thiamine Triphosphorylated Derivatives and Metabolizing Enzymatic Complexes

“…At this time, neither the identity nor the role of this channel was known. It now appears that its core component is the organic anion transporter SLCO2A1, which, in its resting (closed) state, functions as a prostaglandin transporter and in its active (open) state as a channel releasing mainly chloride and ATP [ 57 ]. This channel is thought to be involved in cell volume regulation and purinergic cell-to-cell signaling.…”