Voltage-dependent potassium KCNQ2 channels play a prominent role in the control of neuronal excitability and for their correct functioning they must associate with calmodulin. Indeed, mutations that disrupts this association provokes dominantly inherited human neonatal epilepsy (BFNC). We show here that the pathological effects of these mutants are due to the retention of the channels in the endoplasmic reticulum (ER), altering the number of channels that reach the plasma membrane. Over-expression of a Ca²⁺-binding incompetent calmodulin or sequestering of calmodulin promoted the retention of wild type channels in the ER. Interestingly, elevating the expression of calmodulin partially restores the intracellular distribution of a BFNC mutant. Thus, a direct interaction with Ca²⁺-calmodulin appears to be critical for the function of KCNQ2 potassium channels because it is required for the channels to exit the ER.