期刊
PNAS NEXUS
卷 2, 期 1, 页码 -出版社
OXFORD UNIV PRESS
DOI: 10.1093/pnasnexus/pgac288
关键词
calcium signaling; purinergic receptor; inositol triphosphate receptor; phospholipase C; high throughput screening
Pharmacological modulators of the Ca2+ signaling cascade could be important research tools and therapeutic strategies for human diseases. By screening a diverse chemical library, we identified compounds that can enhance the activation of specific channels and investigated their mechanisms of action using various assays.
Pharmacological modulators of the Ca2+ signaling cascade are important research tools and may translate into novel therapeutic strategies for a series of human diseases. We carried out a screening of a maximally diverse chemical library using the Ca2+-sensitive Cl- channel TMEM16A as a functional readout. We found compounds that were able to potentiate UTP-dependent TMEM16A activation. Mechanism of action of these compounds was investigated by a panel of assays that looked at intracellular Ca2+ mobilization triggered by extracellular agonists or by caged-IP3 photolysis, PIP2 breakdown by phospholipase C, and ion channel activity on nuclear membrane. One compound appears as a selective potentiator of inositol triphosphate receptor type 1 (ITPR1) with a possible application for some forms of spinocerebellar ataxia. A second compound is instead a potentiator of the P2RY2 purinergic receptor, an activity that could promote fluid secretion in dry eye and chronic obstructive respiratory diseases.
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