Membrane proteins of the potassium (K+) channel family play critical roles in controlling neurotransmitter release, neuronal excitability, heart rate, insulin secretion, epithelial electrolyte transport, smooth muscle contraction, and cell volume. The KCNQ subfamily of voltage-gated K+ channels is formed by five members with diverse functional properties. In fact, KCNQ1 subunits underlie the slow repolarizing current (IKs) of the cardiac action potential; mutations in the KCNQ1 gene cause one form of the hereditary cardiac arrhythmia known as Long QT Syndrome. On the other hand, KCNQ2 and KCNQ3 subunits form heteromultimeric complexes whose functional properties recapitulate those of a neuronal-specific K+-selective current termed M-current (IKM); IKM plays a dominant role in controlling neuronal excitability and is characterized by a low activation threshold, slow activation kinetics and absence of inactivation. Mutations in KCNQ2 and KCNQ3 genes are responsible for a rare autosomal-dominant neonatal epilepsy known as Benign Familial Neonatal Convulsions (BFNC). KCNQ4 subunits are also expressed in the nervous system, being altered in some rare forms of autosomal dominant deafness. Finally, KCNQ5 subunits contribute to IKM heterogeneity, co-assembling with other KCNQ subfamily members. The molecular mechanisms responsible for IKM dysfunction prompted by several BFNC mutations are heterogeneous; in fact, while some mutations affect the number of functional channels incorporated in the plasma membrane, possibly by reducing the cytoplasmic protein stability and causing an enhanced proteasomal degradation (1), others may cause permeation or gating defects in normally-assembled channels (2). Beside their involvement in epilepsy, KCNQ2/3 channels appear as promising targets for pharmacological interventions directed against human hyperexcitability. Openers of neuronal KCNQ channels have been shown to be effective in a broad range of in vitro and in vivo seizure models, and are currently undergoing clinical testing. Some of these molecules also posses neuroprotective actions in in vitro and in vivo models of neurodegenerative diseases (3). On the other hand, IKM inhibitors may improve the symptoms of neurodegenerative conditions associated with neurotransmission deficits, such as Alzheimer disease, and are currently undergoing investigation as cognition enhancers. These pharmacological tools have been instrumental in defining the role of presynaptic IKM in neurotransmitter release from central nerve endings (4). In this presentation, we will attempt to describe the heterogeneous consequences on IKM function caused by several BFNC mutations identified by our group, also in the context of the recent progress in the definition of the structural elements involved in gating and permeation in mammalian voltage-gated K+ channels (5). Furthermore, we will explore the pharmacological implications of IKM modulation by drugs and neurotransmitters.