P2Y1 purinergic receptor identified as a diabetes target in a small-molecule screen to reverse circadian β-cell failure

Author:

Marcheva Biliana1ORCID,Weidemann Benjamin J1ORCID,Taguchi Akihiko12,Perelis Mark13,Ramsey Kathryn Moynihan1ORCID,Newman Marsha V1,Kobayashi Yumiko1,Omura Chiaki1,Manning Fox Jocelyn E4,Lin Haopeng4,Macdonald Patrick E4,Bass Joseph1ORCID

Affiliation:

1. Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine

2. Division of Endocrinology, Metabolism, Hematological Science and Therapeutics, Department of Bio-Signal Analysis, Yamaguchi University, Graduate School of Medicine, 1-1-1

3. Ionis Pharmaceuticals, Inc

4. Department of Pharmacology, Alberta Diabetes Institute, University of Alberta

Abstract

The mammalian circadian clock drives daily oscillations in physiology and behavior through an autoregulatory transcription feedback loop present in central and peripheral cells. Ablation of the core clock within the endocrine pancreas of adult animals impairs the transcription and splicing of genes involved in hormone exocytosis and causes hypoinsulinemic diabetes. Here, we developed a genetically sensitized small-molecule screen to identify druggable proteins and mechanistic pathways involved in circadian β-cell failure. Our approach was to generate β-cells expressing a nanoluciferase reporter within the proinsulin polypeptide to screen 2640 pharmacologically active compounds and identify insulinotropic molecules that bypass the secretory defect in CRISPR-Cas9-targeted clock mutant β-cells. We validated hit compounds in primary mouse islets and identified known modulators of ligand-gated ion channels and G-protein-coupled receptors, including the antihelmintic ivermectin. Single-cell electrophysiology in circadian mutant mouse and human cadaveric islets revealed ivermectin as a glucose-dependent secretagogue. Genetic, genomic, and pharmacological analyses established the P2Y1 receptor as a clock-controlled mediator of the insulinotropic activity of ivermectin. These findings identify the P2Y1 purinergic receptor as a diabetes target based upon a genetically sensitized phenotypic screen.

Funder

National Institute of Diabetes and Digestive and Kidney Diseases

National Institute on Aging

Juvenile Diabetes Research Foundation United States of America

Chicago Biomedical Consortium

Manpei Suzuki Diabetes Foundation

Sino-Canadian Studentship

Canadian Institutes of Health Research

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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