Functional Characterization of Native, High-Affinity GABA A Receptors in Human Pancreatic β Cells

• In human pancreatic islets, the neurotransmitter γ-aminobutyric acid (GABA) is an extracellular signaling molecule synthesized by and released from the insulin-secreting β cells. The effective, physiological GABA concentration range within human islets is unknown. Here we use native GABA A receptors in human islet β cells as biological sensors and reveal that 100-1000nM GABA elicit the maximal opening frequency of the single-channels. In saturating GABA, the channels desensitized and stopped working. GABA modulated insulin exocytosis and glucose-stimulated insulin secretion. GABA A receptor currents were enhanced by the benzodiazepine diazepam, the anesthetic propofol and the incretin glucagon-like peptide-1 (GLP-1) but not affected by the hypnotic zolpidem. In type 2 diabetes (T2D) islets, single-channel analysis revealed higher GABA affinity of the receptors. The findings reveal unique GABA A receptors signaling in human islets β cells that is GABA concentration-dependent, differentially regulated by drugs, modulates insulin secretion and is altered in T2D.

Ämnesord

Medical and Health Sciences  (hsv)

Other Medical Sciences  (hsv)

Other Medical Sciences not elsewhere specified  (hsv)

Medicin och hälsovetenskap  (hsv)

Annan medicin och hälsovetenskap  (hsv)

Övrig annan medicin och hälsovetenskap  (hsv)

Medical and Health Sciences  (hsv)

Clinical Medicine  (hsv)

Endocrinology and Diabetes  (hsv)

Medicin och hälsovetenskap  (hsv)

Klinisk medicin  (hsv)

Endokrinologi och diabetes  (hsv)

Nyckelord

GABA

GABA(A) receptor

Pancreatic islet

Type 2 diabetes