Artemisinins Target GABAA Receptor Signaling and Impair α Cell Identity

Abstract

SummaryType 1 diabetes is characterized by the destruction of pancreatic β cells, and generating new insulin-producing cells from other cell types is a major aim of regenerative medicine. One promising approach is transdifferentiation of developmentally related pancreatic cell types, including glucagon-producing α cells. In a genetic model, loss of the master regulatory transcription factor Arx is sufficient to induce the conversion of α cells to functional β-like cells. Here, we identify artemisinins as small molecules that functionally repress Arx by causing its translocation to the cytoplasm. We show that the protein gephyrin is the mammalian target of these antimalarial drugs and that the mechanism of action of these molecules depends on the enhancement of GABAA receptor signaling. Our results in zebrafish, rodents, and primary human pancreatic islets identify gephyrin as a druggable target for the regeneration of pancreatic β cell mass from α cells.

Glucagon antagonism in islet cell proliferation

“…The conversion of α cells to insulin-producing β-like cells in this context may be of great intrigue. Recent work using lineage tracing models has established conversion of α cells to β cells (21), which can be increased by GABA receptor agonism (22,23). At the Touchstone Center, as much as 20% of newly formed β cells may derive from α-cell precursors (24).…”

GABA signaling: A route to new pancreatic β cells

“…Gephyrin is a key regulator of γ-aminobutyric acid (GABA) synthesis and GABA A receptor trafficking. Strikingly, artemether increased β cell numbers in vivo in both mice and zebrafish, and lineage tracing analysis showed that this was due to α to β cell conversion [5]. Artemether-treated clonal α cells (αTC1-6) also displayed Arx exclusion from the nucleus and altered depolarization-induced Ca 2+ dynamics [5], consistent with enhanced GABA A receptor expression.…”

“…Whilst increased Ca 2+ can elicit dramatic changes in cellular phenotype, for example after oocyte fertilization [8], how a decrease in Ca 2+ , as provoked by artemether or GABA A receptor activation (prompting an influx of Cl -ions) [5], could alter gene expression in the α cell in such a dramatic manner remains to be established. Identification of the molecular machinery linking GABAinduced changes in Ca 2+ to altered Arx localization and expression represents an important new challenge.…”

“…Firstly, Li et al [5] established an assay for Arx function, a transcription factor required to maintain α cell phenotype. Overexpression of this factor in the clonal β cell line MIN6 provided the basis of a screen for small molecules which inhibited Arx, consequently increasing insulin gene expression.…”

GABA triggers pancreatic β-like cell neogenesis

“…In collaboration with S. Kubicek's team, we thereby identified 2 distinct compounds acting on the same signaling pathway. 6,7 GABA induces a-cell-mediated b-like cell neogenesis.…”