Expression and function of KCNH2 (HERG) in the human jejunum

Abstract

Previous studies suggest that ether-a-go-go related gene (ERG) KCNH2 potassium channels contribute to the control of motility patterns in the gastrointestinal tract of animal models. The present study examines whether these results can be translated into a role in human gastrointestinal muscles. Messages for two different variants of the KCNH2 gene were detected: KCNH2 V1 human ERG (HERG) (28) and KCNH2 V2 (HERG(USO)) (13). The amount of V2 message was greater than V1 in both human jejunum and brain. The base-pair sequence that gives rise to domains S3-S5 of the channel was identical to that previously published for human KCNH2 V1 and V2. KCNH2 protein was detected immunohistochemically in circular and longitudinal smooth muscle and enteric neurons but not in interstitial cells of Cajal. In the presence of TTX (10(-6) M), atropine (10(-6) M). and l-nitroarginine (10(-4) M) human jejunal circular muscle strips contracted phasically (9 cycles/min) and generated slow waves with superimposed spikes. Low concentrations of the KCNH2 blockers E-4031 (10(-8) M) and MK-499 (3 x 10(-8) M) increased phasic contractile amplitude and the number of spikes per slow wave. The highest concentration of E-4031 (10(-6) M) produced a 10-20 mV depolarization, eliminated slow waves, and replaced phasic contractions with a small tonic contracture. E-4031 (10(-6) M) did not affect [(14)C]ACh release from enteric neurons. We conclude that KCNH2 channels play a fundamental role in the control of motility patterns in human jejunum through their ability to modulate the electrical behavior of smooth muscle cells.

Septal Interstitial Cells of Cajal Conduct Pacemaker Activity to Excite Muscle Bundles in Human Jejunum

“…The rapid Ca 2+ transients in muscle bundles were abolished by nicardipine (1 μM, n=6), suggesting they were generated by Ca 2+ dependent action potentials through activation of L-type Ca 2+ channels. 3,5,6,[17][18][19] In contrast, pacemaker activity in ICC-MY and ICC-SEP was unaffected by nicardipine. 6…”

“…[3][4][5][6][7][8][9][10][11][12] In small mammals, the pacemaker apparatus consists of a two-dimensional network of stellate cells, which lie between the longitudinal muscle (LM) and circular muscle (CM) layers, called the myenteric interstitial cells of Cajal (ICC-MY). 3,7 ICC-MY are connected together and to the neighboring smooth muscle layers by gap junctions.…”

Diminished hERG K+ channel activity facilitates strong human labour contractions but is dysregulated in obese women

“…ARTICLE Blockade of hERG with dofetilide or E-4031 results in depolarization in rat stomach 12 , bovine epididymal 11 and opossum oesophageal 9 smooth muscles. This likely accounts for the increase in contraction frequency created by hERG blockade in most smooth muscle tissues studied 8,10,14 . In contrast, human myometrium was hyperpolarized between APs in the presence of dofetilide, which was accompanied by a decrease in contraction frequency.…”

“…The level of b-subunit protein increases in late pregnancy in mouse uterus 8 but the situation in labour has not been addressed. hERG has been identified in a range of smooth muscle tissues and pharmacological manipulation of its activity has an impact on contractile function [8][9][10][11][12][13][14][15] . Contractile function of uterine smooth muscle is impaired in obese women, who are more likely to experience failure to go into spontaneous labour and failure to progress through to vaginal delivery (18%) compared with normal weight controls (5%) [16][17][18] .…”

“…To test whether hERG regulated AP duration we first recorded membrane potential and contraction simultaneously in strips of myometrium from lean women (body mass index (BMI) o30) at term before labour onset. We used dofetilide (1 mM) and E-4031 (1 mM) as they are selective for hERG blockade 19 and have been commonly used in smooth [8][9][10][11][12][13][14][15] and cardiac 5 muscles. Both blockers caused a striking prolongation of the AP plateau and contraction (Fig.…”