The pharmacology of calcium-activated chloride current is not well developed. Peptides from scorpion venom present potent pharmacological actions on ionic conductance used to characterize the function of channels but can also be helpful to develop organic pharmacological tools. Using electrophysiological recording coupled with calcium measurement, we tested the potent effect of peptides extracted from venom on the calcium-activated chloride current expressed in smooth muscle cells freshly dissociated from rat portal veins. We identified one peptide which selectively inhibited the chloride conductance without effects on either calcium signaling or calcium and potassium currents expressed in this cell type. The synthetic peptide had the same affinity, but the chemical modification of the amino acid sequence altered the efficiency to inhibit the calcium-activated chloride conductance.
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http://dx.doi.org/10.3390/toxins14110780 | DOI Listing |
Br J Pharmacol
January 2025
Department of Pharmacology, University of Oxford, Oxford, UK.
Background And Purpose: TMEM16A chloride channels constitute a depolarising mechanism in arterial smooth muscle cells (SMCs) and contractile cerebral pericytes. TMEM16A pharmacology is incompletely defined. We elucidated the mode of action and selectivity of a recently identified positive allosteric modulator of TMEM16A (PAM_16A) and of a range of TMEM16A inhibitors.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
January 2025
National Key Laboratory of Space Medicine, China Astronaut Research and Training Center, Beijing 100094, China.
TMEM16A, a key calcium-activated chloride channel, is crucial for many physiological and pathological processes such as cancer, hypertension, and osteoporosis, etc. However, the regulatory mechanism of TMEM16A is poorly understood, limiting the discovery of effective modulators. Here, we unveil an allosteric gating mechanism by presenting a high-resolution cryo-EM structure of TMEM16A in complex with a channel inhibitor that we identified, Tamsulosin, which is resolved at 2.
View Article and Find Full Text PDFJ Exp Zool A Ecol Integr Physiol
December 2024
Departement of Biology, Faculty of Science, Academic Assembly, University of Toyama, Gofuku, Toyama, Japan.
In euryhaline teleosts, the cystic fibrosis transmembrane conductance regulator (CFTR) in seawater (SW)-type chloride cells facilitates apical Cl secretion for SW adaptation, while alternative Cl excretion pathways remain understudied. This study investigates the role of the calcium-activated chloride channel, Anoctamin 1 (ANO1), in the gills of the euryhaline Japanese medaka (Oryzias latipes) under hyperosmolality and cortisol (CORT) influence. Acclimation to artificial SW, NaCl, mannitol, or glucose significantly upregulated ANO1 and CFTR mRNA expression in gills, unlike urea treatment.
View Article and Find Full Text PDFAm J Physiol Gastrointest Liver Physiol
February 2025
Arizona College of Osteopathic Medicine, Midwestern University, Glendale, Arizona, United States.
The goal of this study was to determine whether the influence of a high-fat high-sugar diet (Western diet) on intestinal function and health was reversible. We measured transepithelial short circuit current (), across freshly isolated segments of jejunum from male C57Bl/6J mice randomly assigned to one of the following groups for the study duration: high-fat high-sugar diet for 24 wk (HFHS), HFHS diet for 12 wk then switched to standard chow and water for a further 12 wk (Std), and lean controls (standard chow and water for 24 wk). At the completion of the study, segments of jejunum were frozen for Western blot determination of key proteins involved in secretory and absorptive functions, as well as senescence.
View Article and Find Full Text PDFElife
December 2024
Department of Gastroenterology and Hepatology, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, Chengdu, China.
Bestrophin isoform 4 () is a newly identified subtype of the calcium-activated chloride channel family. Analysis of colonic epithelial cell diversity by single-cell RNA-sequencing has revealed the existence of a cluster of + mature colonocytes in humans. However, if the role of is involved in regulating tumour progression remains largely unknown.
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