Expression and function of KCNH2 (HERG) in the human jejunum.
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.
Department of Physiology, University of Nevada School of Medicine, Reno, Nevada 89557, USA.
A M
AM
Farrelly
S
S
Ro
B P
BP
Callaghan
M A
MA
Khoyi
N
N
Fleming
B
B
Horowitz
K M
KM
Sanders
K D
KD
Keef
D000109:Acetylcholine / Q000494:pharmacology; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D001483:Base Sequence; D001578:Benzopyrans / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D005786:Gene Expression Regulation; D006801:Humans; D066298:In Vitro Techniques; D007583:Jejunum / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000235:genetics* / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated; D011189:Potassium Chloride / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D013997:Time Factors; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG
D001578:Benzopyrans; D015220:Calcium Channels; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D010880:Piperidines; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011725:Pyridines; D012333:RNA, Messenger; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; C063968:E 4031; C087257:L 706000; D011189:Potassium Chloride; D000109:Acetylcholine; D011188:Potassium