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.
Highlights
ATP is produced and consumed at high rates inside cells
SLCO2A1 can be added to the class of bimodal channel/transporter proteins [122], which comprises TMEM16 family members, both Ca2+ -activated Cl− channels and lipid scramblases [123]; ClC family proteins known to function as chloride channels and Cl− /H+ exchangers [124,125,126]; excitatory amino acid transporter (EAAT) proteins of the SLC1A family providing a channel pathway for anions within the same molecule [127]; and SLC26A3/6 serving as chloride/bicarbonate exchangers or Cl− channels depending on ionic conditions [128]
The maxi-anion channels represent a heterogeneous population of ion-transporting pathways in which the phenotype of Maxi-Cl with distinct biophysical profile accounts for a majority of reports
Summary
ATP is produced and consumed at high rates inside cells. The resting intracellular ATP concentration is about 1.3 mM in cultured HeLa cells [1], which is close to the ATP content in other cultured cell lines, such as MIN6 (~1 mM) and COSm6 (~1.4 mM) [2,3]. If an ion channel has a pore with poor or, preferably, anionic selectivity and the size is large enough to provide physical passage of the nucleotide, it could serve as an electrogenic pathway for ATP. It should be noted that a large concentration difference between cytosol and external spaces, together with a negative potential inside the cells, provides a very favorable outwardly directed electrochemical potential gradient for conductive ATP release. Acknowledging the contributions of every mentioned conductive pathway in the regulated ATP release, here we shall focus on the maxi-anion channels. We shall briefly outline the main properties of MACs and focus on the molecular identity and partners
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