The suppression of calmodulin binding in Q2/Q3 heterotetramers (that make up the potassium M-current), leads to a complete loss of function because these channels fail to reach the plasma membrane.

We have found that two mutations linked to Benign Familial Neonatal Convulsions (BFNC) partially interfere with CaM binding and cause a partial reduction of the current, a reduction in the number of channels at the plasma membrane, and an increase in the number of channels that colocalize with an ER marker.

KCNQ2 subunits are distributed into three compartments: ER, punctuate intracellular structures, and plasma membrane. Clusters of positively charged residues reminiscent of retention/retrieval signals are present in helices A and B, and close to helix C. Our current working hypothesis is that upon heteromerization a retention signal within or closer to the assembly domain is masked, and that calmodulin conceals additional signals that lead to the stabilization of the populations of channels outside the ER. Disruption of this interaction leads to a reduction in the number of channels at the membrane, with the consequent reduction in function, and can lead to epilepsy in humans.