The maxi-anion channel: a classical channel playing novel roles through an unidentified molecular entity

Abstract

The maxi-anion channel is widely expressed and found in almost every part of the body. The channel is activated in response to osmotic cell swelling, to excision of the membrane patch, and also to some other physiologically and pathophysiologically relevant stimuli, such as salt stress in kidney macula densa as well as ischemia/ hypoxia in heart and brain. Biophysically, the maxi-anion channel is characterized by a large single-channel conductance of 300-400 pS, which saturates at 580-640 pS with increasing the Cl -concentration. The channel discriminates well between Na ? and Cl -, but is poorly selective to other halides exhibiting weak electric-field selectivity with an Eisenman's selectivity sequence I. The maxi-anion channel has a wide pore with an effective radius of *1.3 nm and permits passage not only of Cl -but also of some intracellular large organic anions, thereby releasing major extracellular signals and gliotransmitters such as glutamate -and ATP 4-. The channel-mediated efflux of these signaling molecules is associated with kidney tubuloglomerular feedback, cardiac ischemia/hypoxia, as well as brain ischemia/hypoxia and excitotoxic neurodegeneration. Despite the ubiquitous expression, well-defined properties and physiological/pathophysiological significance of this classical channel, the molecular entity has not been identified. Molecular identification of the maxi-anion channel is an urgent task that would greatly promote investigation in the fields not only of anion channel but also of physiological/pathophysiological signaling in the brain, heart and kidney.

Vesicular and conductive mechanisms of nucleotide release

“…An ATP-conductive large conductance anion channel was first described in murine mammary C127i cells and subsequently found in a variety of tissues and cell types, including cardiomyocytes, astrocytes, and kidney macula densa (reviewed in [97,98]). Maxi anion channels exhibit large single-channel conductance of 300-400 pS, have a wide pore (effective radius of~1.3 nm), discriminate between Na + and halides, and allow the passage of small organic anions, including signaling molecules such as glutamate, ATP, and UTP [97][98][99][100].…”

“…Maxi anion channels exhibit large single-channel conductance of 300-400 pS, have a wide pore (effective radius of~1.3 nm), discriminate between Na + and halides, and allow the passage of small organic anions, including signaling molecules such as glutamate, ATP, and UTP [97][98][99][100]. Maxi anion channels are activated by osmotic cell swelling, ischemia/hypoxia, and in response to excision of the membrane patch, and are inhibited by Gd 3+ and by a number of anion channel blockers of relative selectivity, such as DIDS, NPPB [5-nitro-2-(3-phenylpropylamino)benzoic acid], SITS (4-acetamido-4′-isothiocyanatostilben-2,2′-disulfonate), and DPC (diphenylamine-2-carboxylate), but not by glybenclamide [98]. The involvement of maxi ion channels in the cellular release of ATP is supported by the observation that cells exhibiting maxi ion channel activity display osmotic cell swelling-evoked release of ATP, in a SITS-, NPPB-, and Gd 3+ -sensitive manner [98].…”

“…Maxi anion channels are activated by osmotic cell swelling, ischemia/hypoxia, and in response to excision of the membrane patch, and are inhibited by Gd 3+ and by a number of anion channel blockers of relative selectivity, such as DIDS, NPPB [5-nitro-2-(3-phenylpropylamino)benzoic acid], SITS (4-acetamido-4′-isothiocyanatostilben-2,2′-disulfonate), and DPC (diphenylamine-2-carboxylate), but not by glybenclamide [98]. The involvement of maxi ion channels in the cellular release of ATP is supported by the observation that cells exhibiting maxi ion channel activity display osmotic cell swelling-evoked release of ATP, in a SITS-, NPPB-, and Gd 3+ -sensitive manner [98]. The molecular identity of the maxi anion channel is not known.…”

“…The potential contribution of TTYH1 and TTYH2 to ATP release has not been investigated. However, two splice variants of TTHY1 (TTYH1-SV and TTYH1-E) failed to produce maxi anion channel currents in excised patches when expressed in null cells [98]. Interestingly, TTHY3 exhibits Ca 2+ -activated Cl − channel activity [108], and has been recently implied in the release of ATP from chemo-attractant-stimulated neutrophils; knocking down TTHY3 via shRNA markedly decreased ATP release from HL60 cells stimulated with the formyl-bacterial peptide fMLP [109].…”

Ligand-gated Ion Channels

“…Maxi Cl -channels are high conductance, anion selective, channels initially characterised in skeletal muscle and subsequently found in many cell types including neurones, glia, cardiac muscle, lymphocytes, secreting and absorbing epithelia, macula densa cells of the kidney and human placenta syncytiotrophoblasts (Sabirov and Okada, 2009). The physiological significance of the maxi Cl -channel is uncertain, but roles in cell volume regulation and apoptosis have been claimed.…”