Allosteric modulation of alternatively spliced Ca²⁺-activated Cl^- channels TMEM16A by PI(4,5)P₂ and CaMKII.

ABSTRACT: Transmembrane 16A (TMEM16A, anoctamin1), 1 of 10 TMEM16 family proteins, is a Cl^- channel activated by intracellular Ca²⁺ and membrane voltage. This channel is also regulated by the membrane phospholipid phosphatidylinositol 4,5-bisphosphate [PI(4,5)P₂]. We find that two splice variants of TMEM16A show different sensitivity to endogenous PI(4,5)P₂ degradation, where TMEM16A(ac) displays higher channel activity and more current inhibition by PI(4,5)P₂ depletion than TMEM16A(a). These two channel isoforms differ in the alternative splicing of the c-segment (exon 13). The current amplitude and PI(4,5)P₂ sensitivity of both TMEM16A(ac) and (a) are significantly strengthened by decreased free cytosolic ATP and by conditions that

SUBMITTER: Ko W 

PROVIDER: S-EPMC7720229 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature