Molecular Identity of the M‐Channel

The M-current is a slowly activating and slowly deactivating potassium conductance that plays a critical role in determining the subthreshold electrical excitability of neurons (1-3). The M-current was first described in peripheral sympathetic neurons (4,5), where it is inhibited by stimulation of muscarinic acetylcholine receptors. Inhibition of the M-current and its subsequent effects on neuronal firing properties was one of the first clear descriptions of the mechanism by which neuromodulatory neurotransmitters act in the nervous system (4). Differential expression of the M-current produces subtypes of sympathetic neurons with distinct firing patterns (3). Sympathetic neurons that express the M-current have phasic firing properties, whereas neurons that lack the M-current have tonic firing properties. The M-current also is expressed in many neurons in the central nervous system (1). The molecular identity of the channels that underlie the M-current has recently been determined (6). In sympathetic neurons the M-current is formed by heteromultimers of the KCNQ2 and KCNQ3 potassium channel subunits. The KCNQ subfamily of potassium channel genes contains four members and is unusual because all four genes have been linked to human genetic diseases. The KC.NQ2 and KCNQ3 genes have both been linked to an inherited autosomal dominant epilepsy (7-9). The very similar phenotypes produced by mutation of either of these two distinct genes (10) can be explained by the observation that both gene products are required to produce full expression of functional M-channels (6). The KCNQ2+KCNQ3 channels have closely comparable properties to the native M-channel. The KCNQ2+KCNQ3 channel is the only known potassium channel that can reproduce the unique kinetic properties of the native M-current (6). The pharmacologic properties of the native M-current and the KCNQ2+KCNQ3 channel also are very similar. in particular, the compound XE991 has been shown to be a highly selective blocker of both the M-current and KCNQ channels (6). In addition, the KCNQ2 gene is the only known potassium channel gene expressed in a pattern that parallels the distribution of the M-current in peripheral sympathetic ganglia (6). The KCNQ2 and KCNQ3 genes also are abundantly expressed in the CNS, and it is likely that the KCNQ2+KCNQ3 subunits contribute to the M-current in many central neurons. The M-current, together with the calcium-activated potassium current known as the after-hyperpolarization current, are thought to be the two prirnnry determinants of neuronal firing patterns (2,3). The critical role of the M-current in controlling neuronal excitability is demonstrated in Fig. 1. After blockade of the M-current with XE991, a phasic firing sympathetic neuron is converted to a tonic firing pattern. The cell is considerably more excitable due to the inhibition of the subthreshold M-current. The strong effect of the M-current on neuronal excitability is consistent with the linkage of the KCNQ2 and KCNQ3 genes to an inherited epilepsy (7-9). Identification of the physiologic function of the channel encoded by the KCNQ2 and KCNQ3 genes may facilitate the development of symptomatic treatments for several epilepsies. In particular, compounds that act as enhancers of M-current function may have potential as antiepileptic drugs by dampening intrinsic electrical excitability.