An M 2 ‐like muscarinic receptor enhances a delayed rectifier K + current in rat sympathetic neurones

Background and purpose: Resting superior cervical ganglion (SCG) neurones are phasic cells that switch to a tonic mode of firing upon muscarinic receptor stimulation. This effect is partially due to the muscarinic inhibition of the M‐current. Because delayed rectifier K + channels are essential to sustain tonic firing in central neurones, we asked whether the delayed rectifier current I KV in SCG neurones was modulated by the muscarinic receptors expressed in these cells. Experimental approach: Whole‐cell patch‐clamp records of M‐current and I KV were done in cultured or acutely dissociated rat SCG neurones. To characterize the receptor that regulates I KV , cells were bathed with muscarinic agonists and antagonists, relatively specific for receptor subtypes. Key results: The muscarinic agonist oxotremorine‐M (Oxo‐M) enhanced I KV by ∼46% relative to its basal value. This effect remained unaltered when M‐current was suppressed by linopirdine or Ba 2+ . Enhancement of I KV was insensitive to the M 1 ‐antagonist pirenzepine, whereas it was inhibited (∼60%) by the M 2/4 ‐antagonist himbacine. Further, the relatively specific M 2 ‐agonist bethanechol was as potent as Oxo‐M in enhancing I KV . The modulation of I KV was insensitive to pertussis toxin (PTX), but was severely attenuated when internal ATP was replaced by its non‐hydrolysable analogue AMP‐PNP. Conclusions and Implications: These results suggest that an M 2 ‐like muscarinic receptor couples to a PTX‐insensitive G‐protein and to an ATP‐dependent pathway to enhance I KV . Modulation of I KV must be taken into consideration in order to understand more precisely how muscarinic receptors acting on different ion channels regulate sympathetic excitability. British Journal of Pharmacology (2006) 149 , 441–449. doi: 10.1038/sj.bjp.0706874