Pharmacological potentiators of the calcium signaling cascade identified by high-throughput screening
Authors: Michele Genovese, Daniela Guidone, Martina Buccirossi, Anna Borrelli, Alejandra Rodriguez-Gimeno, Fabio Bertozzi, Tiziano Bandiera, Luis J V Galietta
Year: 2023
Sources: PNAS Nexus
Abstract:
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.
Significance Statement
Modulation of the Ca2+ signaling pathway with selective pharmacological agents is an important approach to understand the underlying molecular mechanisms and a possible therapeutic strategy for many human diseases. Our study has revealed novel small molecules that act on the pathway at different levels. In particular, they include allosteric potentiators of the purinergic receptor P2RY2 and the inositol triphosphate receptor type 1 (ITPR1), two targets for which there were no available modulators acting with this mechanism. These novel pharmacological agents will allow experiments to selectively modulate the corresponding targets for scientific purposes. They will also be the starting point to develop selective drugs.
Significance Statement
Modulation of the Ca2+ signaling pathway with selective pharmacological agents is an important approach to understand the underlying molecular mechanisms and a possible therapeutic strategy for many human diseases. Our study has revealed novel small molecules that act on the pathway at different levels. In particular, they include allosteric potentiators of the purinergic receptor P2RY2 and the inositol triphosphate receptor type 1 (ITPR1), two targets for which there were no available modulators acting with this mechanism. These novel pharmacological agents will allow experiments to selectively modulate the corresponding targets for scientific purposes. They will also be the starting point to develop selective drugs.
Category: journals