Disease relevance of CLNS1A

• Glucose induces anion conductance and cytosol-to-membrane transposition of ICln in INS-1E rat insulinoma cells [1].

High impact information on CLNS1A

• Purified, water-soluble ICln is able to insert into lipid bilayers to form ion channels [2].
• A major phosphorylation site for all three kinases is Ser-45 within the ICln PH domain [2].
• ICln is a multifunctional protein involved in regulatory mechanisms as different as membrane ion transport and RNA splicing [2].
• ICln, a novel integrin alphaIIbbeta3-associated protein, functionally regulates platelet activation [3].
• To address this question, we disrupted the ICln gene in embryonic stem cells [4].

Biological context of CLNS1A

• By fluorescence in situ hybridization a copy carrying introns with a putative length of 19 kb was located at chromosome 11 on position 11q13.5-q14.1 (CLNS1A) [5].
• Two different loci that carry the coding region for ICln were identified in the human genome [5].
• We found that murine embryos lacking ICln die early in gestation (between stages E3.5 and E7.5) [4].
• ICln: a chloride channel paramount for cell volume regulation [6].
• In contrast to ICl,swell, inactivation kinetics of ICln were pH independent and extracellular cAMP blocked only the outward ICln component [7].

Anatomical context of CLNS1A

• Immunocytochemistry experiments showed the presence of ICln protein in the cytosol and in the plasma membrane [8].
• Thus, it is unlikely that pICln forms the channel that is responsible for the ICln current in Xenopus oocytes [9].
• Experiments designed to knock down the ICln protein in NIH 3T3 fibroblasts as well as in epithelial cells led to the conclusion that this protein is crucially involved in volume regulation after cytoplasmic swelling [10].
• A unique feature of ICln is the distinct sensitivity of these channels for nucleotides and nucleoside analogues added to the extracellular fluid [6].
• We investigated the swelling-induced chloride current in fibroblasts, which we demonstrated is closely related or identical to a cloned epithelial chloride channel, ICln: This chloride channel can be blocked by nucleotides [11].

Associations of CLNS1A with chemical compounds

• In parallel, a cell-permeable peptide corresponding to the potential integrin-recognition domain on ICln (AKFEEE, 10-100 microm) also inhibits platelet function [3].
• pICln is a protein that induces an outwardly rectifying, nucleotide-sensitive chloride current (ICln) when expressed in Xenopus oocytes, but its precise function (plasma-membrane anion channel versus cytosolic regulator of a channel) remains controversial [9].
• Outward rectification and the discrimination between NO3- and Cl- were more pronounced for ICln [7].
• 5. The binding site for the two phenol derivatives onto ICln seems to be distinct but closely related to the nucleotide binding site identified as G x G x G, a glycine repeat located at the predicted outer mouth of the ICln channel protein [12].

Other interactions of CLNS1A

• Characterization of the human gene coding for the swelling-dependent chloride channel ICln at position 11q13.5-14.1 (CLNS1A) and further characterization of the chromosome 6 (CLNS1B) localization [13].
• However, other possible roles for ICln in potential regulatory mechanisms have been postulated, as diverse as regulator of cell morphology by interacting with the Skb1 protein and/or interaction with core spliceosomal proteins [14].
• By using full-length HRpICln cDNA (approx. 1.2 kb) to probe human lymphocyte metaphase-chromosome spreads, the location of the human ICln gene was mapped to 11q13 by fluorescence in situ hybridization analysis [15].

Analytical, diagnostic and therapeutic context of CLNS1A

• We verified the presence of ICln in human platelets by PCR, Western blots, immunohistochemistry, and its co-association with alpha(IIb)beta(3) by surface plasmon resonance [3].
• Western blot analysis revealed an increase of ICln in the membrane under hypotonic conditions, an event possibly related to the activation of Cl(-) channels [8].

References