M-channels are low-threshold, voltage-gated non-inactivating potassium channels that regulate the excitability of a variety of peripheral and central neurons and axons. They are inhibited by activating Gq-coupled receptors such as M1-muscarinic acetylcholine receptors (mAChRs), leading to an increased neural excitability. They are also blocked by linopirdine and XE991 and their opening facilitated by retigabine. M-channels are composed of Kv7 (KCNQ) channel subunits. Most native M-channels are formed from Kv7.2/7.3 heteromers (2+2 stoichiometry), sometimes by Kv7.2 homomers, but all Kv7 subunits form M- channels when expressed as homomers. Opening of M-channels requires membrane PIP2 and their inhibition by mAChRs is due to PIP2 depletion. However, they are also closed (via channel- attached calmodulin) by raising intracellular Ca; this is normally responsible for their inhibition by bradykinin. Closure may also be facilitated by PKC-mediated channel phosphorylation, via a channel-attached AKAP. Mutations of human KCNQ2 or KCNQ3 genes gives rise to juvenile epilepsy and drugs that block M-channels enhance transmitter release, increase neural excitability and are pro-epileptic; drugs that enhance M-channel activity are anti-convulsant and anti-nnociceptive. Recent work concerning their composition, localization in peripheral and central neurons, and regulation will be described.

Suppurted by the UK MRC, Wellcome Trust and EU FP6.