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HIGHLIGHTS- Calmodulin-dependent Kv7.2 current density without the need of binding calcium.    - Kv7.2 current density increase is accompanied with resistance to PI(4,5)P 2  depletion.    - Kv7.3 current density is insensitive to calmodulin elevation.    - Kv7.3 is more sensitive to PI(4,5)P 2  depletion in the presence of calmodulin.    - Apo-calmodulin influences PI(4,5)P 2  dependence in a subunit specific manner.The identification and understanding of critical factors regulating M-current functional density, whose main components are Kv7.2 and Kv7.3 subunits, has profound pathophysiological impact given the important role of the M-current in neuronal excitability control. We report the increase in current density of Kv7.2 channels by calmodulin (CaM) and by a mutant CaM unable to bind Ca 2+  (CaM 1234 ) revealing that this potentiation is calcium independent. Furthermore, after co-expressing a CaM binding protein (CaM sponge) to reduce CaM cellular availability, Kv7.2 current density was reduced. Current inhibition after transient depletion of the essential Kv7 co-factor phosphatidylinositol-4,5-bisphosphate (PI(4,5)P 2 ) by activating  Danio rerio  voltage sensitive phosphatase (DrVSP) was blunted by co-expressing CaM 1234  or the CaM sponge. In addition, CaM-dependent potentiation was occluded by tonic elevation of PI(4,5)P 2  levels by PI(4)P5-kinase (PIP5K) expression. In contrast to the effect on homomeric Kv7.2 channels, CaM 1234  failed to potentiate heteromeric Kv7.2/3 or homomeric Kv7.3 channels. Sensitivity to PI(4,5)P 2  depletion of Kv7.2/3 channels was increased after expression of CaM 1234  or the CaM sponge, while that of homomeric Kv7.3 was unaltered. Altogether, the data reveal that apo-CaM influences PI(4,5)P 2  dependence of Kv7.2, Kv7.2/3, and of Kv7.3 channels in a subunit specific manner.

Differential Regulation of PI(4,5)P2 Sensitivity of Kv7.2 and Kv7.3 Channels by Calmodulin