BIOMAT Database Logo BIOMAT Database Logo

ANO1 in intramuscular interstitial cells of Cajal plays a key role in the generation of slow waves and tone in the internal anal sphincter. 2017

C A Cobine, and E E Hannah, and M H Zhu, and H E Lyle, and J R Rock, and K M Sanders, and S M Ward, and K D Keef
Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, Reno, NV, 89557, USA.

The internal anal sphincter develops tone important for maintaining high anal pressure and continence. Controversy exists regarding the mechanisms underlying tone development. We examined the hypothesis that tone depends upon electrical slow waves (SWs) initiated in intramuscular interstitial cells of Cajal (ICC-IM) by activation of Ca2+ -activated Cl- channels (ANO1, encoded by Ano1) and voltage-dependent L-type Ca2+ channels (CavL , encoded by Cacna1c). Measurement of membrane potential and contraction indicated that ANO1 and CavL have a central role in SW generation, phasic contractions and tone, independent of stretch. ANO1 expression was examined in wildtype and Ano1/+egfp mice with immunohistochemical techniques. Ano1 and Cacna1c expression levels were examined by quantitative PCR in fluorescence-activated cell sorting. ICC-IM were the predominant cell type expressing ANO1 and the most likely candidate for SW generation. SWs in ICC-IM are proposed to conduct to smooth muscle where Ca2+ entry via CavL results in phasic activity that sums to produce tone. The mechanism underlying tone generation in the internal anal sphincter (IAS) is controversial. We examined the hypothesis that tone depends upon generation of electrical slow waves (SWs) initiated in intramuscular interstitial cells of Cajal (ICC-IM) by activation of Ca2+ -activated Cl- channels (encoded by Ano1) and voltage-dependent L-type Ca2+ channels (encoded by Cacna1c). Phasic contractions and tone in the IAS were nearly abolished by ANO1 and CavL antagonists. ANO1 antagonists also abolished SWs as well as transient depolarizations that persisted after addition of CavL antagonists. Tone development in the IAS did not require stretch of muscles, and the sensitivity of contraction to ANO1 antagonists was the same in stretched versus un-stretched muscles. ANO1 expression was examined in wildtype and Ano1/+egfp mice with immunohistochemical techniques. Dual labelling revealed that ANO1 expression could be resolved in ICC but not smooth muscle cells (SMCs) in the IAS and rectum. Ano1, Cacna1c and Kit gene expression were the same in extracts of IAS and rectum muscles. In IAS cells isolated with fluorescence-activated cell sorting, Ano1 expression was 26.5-fold greater in ICC than in SMCs while Cacna1c expression was only 2-fold greater in SMCs than in ICC. These data support a central role for ANO1 and CavL in the generation of SWs and tone in the IAS. ICC-IM are the probable cellular candidate for ANO1 currents and SW generation. We propose that ANO1 and CavL collaborate to generate SWs in ICC-IM followed by conduction to adjacent SMCs where phasic calcium entry through CavL sums to produce tone.

UI MeSH Term Description Entries
D008297 Male Males
D008564 Membrane Potentials The voltage differences across a membrane. For cellular membranes they are computed by subtracting the voltage measured outside the membrane from the voltage measured inside the membrane. They result from differences of inside versus outside concentration of potassium, sodium, chloride, and other ions across cells' or ORGANELLES membranes. For excitable cells, the resting membrane potentials range between -30 and -100 millivolts. Physical, chemical, or electrical stimuli can make a membrane potential more negative (hyperpolarization), or less negative (depolarization). Resting Potentials,Transmembrane Potentials,Delta Psi,Resting Membrane Potential,Transmembrane Electrical Potential Difference,Transmembrane Potential Difference,Difference, Transmembrane Potential,Differences, Transmembrane Potential,Membrane Potential,Membrane Potential, Resting,Membrane Potentials, Resting,Potential Difference, Transmembrane,Potential Differences, Transmembrane,Potential, Membrane,Potential, Resting,Potential, Transmembrane,Potentials, Membrane,Potentials, Resting,Potentials, Transmembrane,Resting Membrane Potentials,Resting Potential,Transmembrane Potential,Transmembrane Potential Differences
D008810 Mice, Inbred C57BL One of the first INBRED MOUSE STRAINS to be sequenced. This strain is commonly used as genetic background for transgenic mouse models. Refractory to many tumors, this strain is also preferred model for studying role of genetic variations in development of diseases. Mice, C57BL,Mouse, C57BL,Mouse, Inbred C57BL,C57BL Mice,C57BL Mice, Inbred,C57BL Mouse,C57BL Mouse, Inbred,Inbred C57BL Mice,Inbred C57BL Mouse
D008822 Mice, Transgenic Laboratory mice that have been produced from a genetically manipulated EGG or EMBRYO, MAMMALIAN. Transgenic Mice,Founder Mice, Transgenic,Mouse, Founder, Transgenic,Mouse, Transgenic,Mice, Transgenic Founder,Transgenic Founder Mice,Transgenic Mouse
D009119 Muscle Contraction A process leading to shortening and/or development of tension in muscle tissue. Muscle contraction occurs by a sliding filament mechanism whereby actin filaments slide inward among the myosin filaments. Inotropism,Muscular Contraction,Contraction, Muscle,Contraction, Muscular,Contractions, Muscle,Contractions, Muscular,Inotropisms,Muscle Contractions,Muscular Contractions
D009130 Muscle, Smooth Unstriated and unstriped muscle, one of the muscles of the internal organs, blood vessels, hair follicles, etc. Contractile elements are elongated, usually spindle-shaped cells with centrally located nuclei. Smooth muscle fibers are bound together into sheets or bundles by reticular fibers and frequently elastic nets are also abundant. (From Stedman, 25th ed) Muscle, Involuntary,Smooth Muscle,Involuntary Muscle,Involuntary Muscles,Muscles, Involuntary,Muscles, Smooth,Smooth Muscles
D005260 Female Females
D000075369 Anoctamin-1 An anoctamin chloride channel expressed at high levels in the liver, skeletal muscle, and gastrointestinal muscles that functions in transepithelial anion transport and smooth muscle contraction. It is essential for the function of the INTERSTITIAL CELLS OF CAJAL and plays a major role in chloride conduction by airway epithelial cells and in tracheal cartilage development. TMEM16A Protein,Transmembrane Protein 16A,Anoctamin 1
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001003 Anal Canal The terminal segment of the LARGE INTESTINE, beginning from the ampulla of the RECTUM and ending at the anus. Anal Gland, Human,Anal Sphincter,Anus,Anal Gland,Anal Glands, Human,Detrusor External Sphincter,External Anal Sphincter,Internal Anal Sphincter,Anal Sphincter, External,Anal Sphincter, Internal,Anal Sphincters,Detrusor External Sphincters,External Anal Sphincters,Human Anal Gland,Human Anal Glands,Internal Anal Sphincters,Sphincter, Anal,Sphincter, Detrusor External,Sphincter, External Anal,Sphincter, Internal Anal,Sphincters, Anal

Related Publications

C A Cobine, and E E Hannah, and M H Zhu, and H E Lyle, and J R Rock, and K M Sanders, and S M Ward, and K D Keef
Interstitial cells of Cajal modulate the tone of the human internal anal sphincter in vitro.
March 2014, Diseases of the colon and rectum,
C A Cobine, and E E Hannah, and M H Zhu, and H E Lyle, and J R Rock, and K M Sanders, and S M Ward, and K D Keef
Distribution of interstitial cells of Cajal in the internal anal sphincter of patients with internal anal sphincter achalasia and Hirschsprung disease.
September 2003, Archives of pathology & laboratory medicine,
C A Cobine, and E E Hannah, and M H Zhu, and H E Lyle, and J R Rock, and K M Sanders, and S M Ward, and K D Keef
A novel intramuscular Interstitial Cell of Cajal is a candidate for generating pacemaker activity in the mouse internal anal sphincter.
June 2020, Scientific reports,
C A Cobine, and E E Hannah, and M H Zhu, and H E Lyle, and J R Rock, and K M Sanders, and S M Ward, and K D Keef
Regional variation in contribution of myenteric and intramuscular interstitial cells of Cajal to generation of slow waves in mouse gastric antrum.
May 2002, The Journal of physiology,
C A Cobine, and E E Hannah, and M H Zhu, and H E Lyle, and J R Rock, and K M Sanders, and S M Ward, and K D Keef
Relationship between interstitial cells of Cajal, fibroblast-like cells and inhibitory motor nerves in the internal anal sphincter.
April 2011, Cell and tissue research,
C A Cobine, and E E Hannah, and M H Zhu, and H E Lyle, and J R Rock, and K M Sanders, and S M Ward, and K D Keef
Conditional genetic deletion of Ano1 in interstitial cells of Cajal impairs Ca2+ transients and slow waves in adult mouse small intestine.
March 2017, American journal of physiology. Gastrointestinal and liver physiology,
C A Cobine, and E E Hannah, and M H Zhu, and H E Lyle, and J R Rock, and K M Sanders, and S M Ward, and K D Keef
Selective knockout of intramuscular interstitial cells reveals their role in the generation of slow waves in mouse stomach.
March 2001, The Journal of physiology,
C A Cobine, and E E Hannah, and M H Zhu, and H E Lyle, and J R Rock, and K M Sanders, and S M Ward, and K D Keef
Generation of slow waves in membrane potential is an intrinsic property of interstitial cells of Cajal.
August 1999, The American journal of physiology,
C A Cobine, and E E Hannah, and M H Zhu, and H E Lyle, and J R Rock, and K M Sanders, and S M Ward, and K D Keef
Interstitial cells of cajal generate electrical slow waves in the murine stomach.
July 1999, The Journal of physiology,
C A Cobine, and E E Hannah, and M H Zhu, and H E Lyle, and J R Rock, and K M Sanders, and S M Ward, and K D Keef
The functional role of intramuscular interstitial cells of Cajal in the stomach.
January 2011, Journal of smooth muscle research = Nihon Heikatsukin Gakkai kikanshi,
Copied contents to your clipboard!