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Effects of Compounds That Influence I_K (KCNN4) Channels on Afterhyperpolarizing Potentials, and Determination of I_K Channel Sequence, in Guinea Pig Enteric Neurons

¹Department of Anatomy and Cell Biology and Centre for Neuroscience, University of Melbourne, Parkville, Victoria, Australia; ²Department of Basic Veterinary Science, School of Veterinary Sciences, Gifu University, Gifu, Japan; ³The Walter and Eliza Hall Institute, Parkville, Victoria, Australia; and ⁴Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, United Kingdom

Submitted 1 September 2006; accepted in final form 12 January 2007

The late afterhyperpolarizing potential (AHP) that follows the action potential in intrinsic primary afferent neurons of the gastrointestinal tract has a profound influence on their firing patterns. There has been uncertainty about the identity of the channels that carry the late AHP current, especially in guinea pigs, where the majority of the physiological studies have been made. In the present work, the late AHP was recorded with intracellular microelectrodes from myenteric neurons in the guinea pig small intestine. mRNA was extracted from the ganglia to determine the identity of the guinea pig intermediate conductance potassium (I_K) channel gene transcript. The late AHP was inhibited by two blockers of I_K channels, TRAM34 (0.1–1 µM) and clotrimazole (10 µM), and was enhanced by the potentiator of the opening of these channels, DC-EBIO (100 nM). Action potential characteristics were unchanged by TRAM34 or DC-EBIO. The full sequence of the gene transcript and the deduced amino acid sequence were determined from extracts including myenteric ganglia and from bladder urothelium, which is a rich source of I_K channel mRNA. This showed that the guinea pig sequence has a high degree of homology with other mammalian sequences but that the guinea pig channel lacks a phosphorylation site that was thought to be critical for channel regulation. It is concluded that the channels that carry the current of the late afterhyperpolarizing potential in guinea pig enteric neurons are I_K channels.

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