The mechanism and spread of pacemaker activity through myenteric interstitial cells of Cajal in human small intestine.
OBJECTIVE
It has been generally assumed that interstitial cells of Cajal (ICC) in the human gastrointestinal tract have similar functions to those in rodents, but no direct experimental evidence exists to date for this assumption. This is an important question because pathologists have noted decreased numbers of ICC in patients with a variety of motility disorders, and some have speculated that loss of ICC could be responsible for motor dysfunction. Our aims were to determine whether myenteric ICC (ICC-MY) in human jejunum are pacemaker cells and whether these cells actively propagate pacemaker activity.


METHODS
The mucosa and submucosa were removed, and strips of longitudinal muscle were peeled away to reveal the ICC-MY network. ICC networks were loaded with the Ca(2+) indicator fluo-4, and pacemaker activity was recorded via high-speed video imaging at 36.5 degrees C +/- 0.5 degrees C.


RESULTS
Rhythmic, biphasic Ca(2+) transients (6.03 +/- 0.33 cycles/min) occurred in Kit-positive ICC-MY. These consisted of a rapidly propagating upstroke phase that initiated a sustained plateau phase, which was associated with Ca(2+) spikes in neighboring smooth muscle. Pacemaker activity was dependent on inositol 1,4,5-triphosphate receptor-operated stores and mitochondrial function. The upstroke phase of Ca(2+) transients in ICC-MY appeared to result from Ca(2+) influx through dihydropyridine-resistant Ca(2+) channels, whereas the plateau phase was attributed to Ca(2+) release from inositol 1,4,5-triphosphate receptor-operated Ca(2+) stores.


CONCLUSIONS
Each ICC-MY in human jejunum generates spontaneous pacemaker activity that actively propagates through the ICC network. Loss of these cells could severely disrupt the normal function of the human small intestine.
Lee
Hyun-Tai
HT
Department of Physiology & Cell Biology, University of Nevada School of Medicine, Reno, Nevada 89577, USA.
Hennig
Grant W
GW
Fleming
Neal W
NW
Keef
Kathleen D
KD
Spencer
Nick J
NJ
Ward
Sean M
SM
Sanders
Kenton M
KM
Smith
Terence K
TK
D000328:Adult; D001683:Biological Clocks / Q000502:physiology*; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D004594:Electrophysiology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000502:physiology; D007413:Intestinal Mucosa / Q000166:cytology / Q000294:innervation / Q000502:physiology; D007583:Jejunum / Q000166:cytology / Q000294:innervation* / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009197:Myenteric Plexus / Q000166:cytology / Q000502:physiology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009529:Nicardipine / Q000494:pharmacology
D002121:Calcium Channel Blockers; D000697:Central Nervous System Stimulants; D053496:Inositol 1,4,5-Trisphosphate Receptors; D002110:Caffeine; D009529:Nicardipine; D002118:Calcium