Cause for excite-M-ent in adrenal chromaffin cells.

M-current is a non-inactivating K+ current that was first described in sympathetic ganglion neurons where it was inhibited by activation of muscarinic acetylcholine receptors (hence the name ‘M’-current) (Brown & Adams, 1980). Opening of K+ channels tends to hyperpolarize cells, and because M-current is activated at potentials that are subthreshold for action potential firing (often close to the resting potential of cells) it is important in the control of cell excitability. Inhibition of M-current by acetylcholine and a number of other neurotransmitters and peptides promotes action potential firing by causing an increase in membrane resistance and cell depolarization. Closure of M-channels is thought to underlie a slow excitatory postsynaptic potential in sympathetic and hippocampal neurons. However, after more than 20 years of study the signalling pathway(s) that leads to closure of the channels upon receptor activation remain unclear (Brown & Yu, 2000). Heteromeric channels comprised of KCNQ2 and KCNQ3 K+ channel subunits underlie M-current (Wang et al. 1998). Homomeric KCNQ2 or KCNQ3 channels can also produce M-like currents, albeit at a much lower channel density. Furthermore, both KCNQ5 (Brown & Yu, 2000) and Erg1 subunits (Selyanko et al. 2002) may also contribute, increasing the molecular diversity of M-like channels. Mutations in these KCNQ subunits can lead to certain forms of epilepsy underscoring the importance of M-channels in controlling neuronal excitability (Jentsch, 2000). In this issue of The Journal of PhysiologyWallace and colleagues (2002) now show that M-channels are also involved in controlling catecholamine release from the adrenal gland. Catecholamines are synthesized and released from the chromaffin cells of the adrenal medulla and exert widespread physiological actions including the classic ‘fight or flight’ response to stress. The primary trigger for secretion is acetylcholine (ACh) released from the splanchnic nerve terminals in the adrenal medulla. The ACh opens nicotinic acetylcholine receptor channels on the chromaffin cells which depolarize the membrane and lead to Ca2+ entry through voltage-gated Ca2+ channels. Activation of G-protein coupled receptors by circulating or locally released transmitters such as histamine can also elicit catecholamine release. Receptor activation elevates intracellular calcium levels both by release of intracellular Ca2+ stores by inositol trisphosphate, and by sustained influx of extracellular Ca2+. Most if not all of the catecholamine release is dependent upon this extracellular Ca2+ influx which may involve several pathways including voltage-gated Ca2+ channels and store/receptor operated Ca2+ channels (perhaps Icrac or TRP family members) (Zerbes et al. 1998; O'Farrell & Marley, 1999). However, the mechanisms by which receptor activation leads to calcium entry remain poorly understood. Wallace and colleagues now show that M-type K+ channels provide a link between activation of histamine receptors and opening of voltage-gated Ca2+ channels. Application of histamine to chromaffin cells caused a biphasic response. At first histamine induced a transient membrane hyperpolarization, most likely to involve opening of Ca2+-activated K+ channels. Following the hyperpolarization was a sustained depolarization and increase in membrane resistance which led to increased spontaneous action potential activity. Wallace et al. demonstrated that M-channels were open at the resting potential of these cells and that the closure of these channels by activation of H1 histaminergic receptors was responsible, at least in part, for the depolarization and increased excitability that was observed. This paper represents both the first description of M-current in chromaffin cells and the first evidence in any cell type for coupling of histamine receptors to this type of K+ channel. The evidence that M-channels play an important role in the secretory response of adrenal chromaffin cells to histamine is compelling, but is clearly not the whole story. Wallace et al. show that when the M-current was blocked pharmacologically, the depolarization produced by histamine was diminished but not abolished. Another type of K+ channel may be involved in this response but that remains to be clarified. Furthermore, H1 receptors can also inhibit voltage-gated Ca2+ channels in chromaffin cells through a voltage-dependent mechanism involving G-protein βγ subunits and a voltage-independent pathway that bears similarities to the ill defined pathway that suppresses M-channels (Currie & Fox, 2000). Store operated Ca2+ entry may also be involved in the extracellular Ca2+-influx observed: these currents have been shown to augment depolarization-elicited catecholamine release (Fomina & Nowycky, 1999). Ultimately a conglomerate of many subtle actions, including M-channel modulation, will determine the physiological response to histamine. Other transmitters may also activate elements of this signalling pathway. For instance, will ACh released by presynaptic splanchnic neurons also inhibit M-currents via activation of ‘classical’ muscarinic receptors? As for the M-channels themselves, the current recorded in chromaffin cells is small in comparison to most neuronal M-currents. It will be interesting to see whether the small current results from low expression levels or whether chromaffin cells express homomeric channels, which tend to make small currents. Chromaffin cells are generally considered to be a model of presynaptic nerve terminals. Will this analogy hold up for M-currents, i.e. will there be cases where M-currents, localized to presynaptic terminals, modulate release? Interestingly, it appears that KCNQ2 but not KCNQ3 subunits may be expressed presynaptically (Cooper et al. 2000). And of course the ultimate goal for M-channels afficionados remains the elucidation of the complete signalling pathways leading to channel inhibition. After allergies, ulcers and pain, now there's excite-M-ent in the hista-M-ine field.