SPACE DPRuOnVwIDinErDn. Electrical pacemaker activity serves a critical function in gastric motility. Previous studies have determined that interstitial cells of Cajal (ICC), located in the myenteric region of the tunica muscularis of the corpus and antrum, are the primary pacemaker cells in- mammalian gastric muscles. Pacemaker events, originating near the greater curvature of the corpus, spread around and down the stomach to the pyloric sphincter.This activity, known as electrical slow waves, times the occurrence of gastric peristaltic contractions. Proper spread of slow waves depends upon a proximal-to-disjal gradient in the intrinsic frequency of pacemaker activity. Loss of pacemaker activity, emergence of ectopic pacemakers, or defects in slowwave propagation can lead to functional motility disorders of the stomach. This project seeks to understand the pacemaker mechanisms in gastric ICC;Studies will be performed on isolated ICC from the corpus arid antrum to determine the conductance(s) responsible for pacemaker currents and the intracellular events activation of pacemaker currents. We have found that the gastric pacemaker frequency gradient is encoded in ICC from the corpus and antrum, and further experiments will dissect the differences in pacemaker activity of the ICC from these regions to understand the basis for the pacemakerfrequency gradient. We will also determine whether the mechanisms responsible for generation of pacemaker current are required for regeneration of slow waves, and experiments will be performed to understand how electrical pacing from an external current source can affect generation and propagation of slow waves. Experiments to determine the factors involved in regulation of pacemaker .frequency in ICC and to determine the mechanisms, by which various biogenic chemicals affect the timing of .pacemaker events will be performed. This information may provide new insights into the causes (and perhaps cures) for gastric arrhythmias. Basic information about generation, propagation and regulation of pacemaker frequency will be upounded in studies of intact muscles to explore the nature of the gastric'frequency gradient and ho y changes in pacemaker frequency affect the spread of slow waves (i.e. functional coupling) between the corpus and antrum.. New animal models of gastric arrhythmias will be studied to determine how pacemaker abnormalities affect functional coupling.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Hamilton, Frank A
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University of Nevada Reno
Schools of Medicine
United States
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Sanders, Kenton M; Salter, Anna K; Hennig, Grant W et al. (2014) Responses to enteric motor neurons in the gastric fundus of mice with reduced intramuscular interstitial cells of cajal. J Neurogastroenterol Motil 20:171-84
Sanders, Kenton M; Ward, Sean M; Koh, Sang Don (2014) Interstitial cells: regulators of smooth muscle function. Physiol Rev 94:859-907
Bhetwal, Bhupal P; Sanders, Kenton M; An, Changlong et al. (2013) Ca2+ sensitization pathways accessed by cholinergic neurotransmission in the murine gastric fundus. J Physiol 591:2971-86
Sanders, Kenton M; Zhu, Mei Hong; Britton, Fiona et al. (2012) Anoctamins and gastrointestinal smooth muscle excitability. Exp Physiol 97:200-6
Sanders, Kenton M; Koh, Sang Don; Ro, Seungil et al. (2012) Regulation of gastrointestinal motility--insights from smooth muscle biology. Nat Rev Gastroenterol Hepatol 9:633-45
Bayguinov, O; Hennig, G W; Sanders, K M (2011) Movement based artifacts may contaminate extracellular electrical recordings from GI muscles. Neurogastroenterol Motil 23:1029-42, e498
Rhee, Poong-Lyul; Lee, Ji Yeon; Son, Hee Jung et al. (2011) Analysis of pacemaker activity in the human stomach. J Physiol 589:6105-18
Zhu, Mei Hong; Sung, In Kyung; Zheng, Haifeng et al. (2011) Muscarinic activation of Ca2+-activated Cl- current in interstitial cells of Cajal. J Physiol 589:4565-82
Sanders, Kenton M; Hwang, Sung Jin; Ward, Sean M (2010) Neuroeffector apparatus in gastrointestinal smooth muscle organs. J Physiol 588:4621-39
Ro, Seungil; Park, Chanjae; Jin, Jingling et al. (2010) A model to study the phenotypic changes of interstitial cells of Cajal in gastrointestinal diseases. Gastroenterology 138:1068-78.e1-2

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