Abstract
The GLP-1 receptor is a Class B heptahelical G-protein-coupled receptor that stimulates
cAMP production in pancreatic β-cells. GLP-1 utilizes this receptor to activate two
distinct classes of cAMP-binding proteins: protein kinase A (PKA) and the Epac family
of cAMP-regulated guanine nucleotide exchange factors (cAMPGEFs). Actions of GLP-1
mediated by PKA and Epac include the recruitment and priming of secretory granules,
thereby increasing the number of granules available for Ca2+-dependent exocytosis. Simultaneously, GLP-1 promotes Ca2+ influx and mobilizes an intracellular source of Ca2+. GLP-1 sensitizes intracellular Ca2+ release channels (ryanodine and IP3 receptors) to stimulatory effects of Ca2+, thereby promoting Ca2+-induced Ca2+ release (CICR). In the model presented here, CICR activates mitochondrial dehydrogenases,
thereby upregulating glucose-dependent production of ATP. The resultant increase in
cytosolic [ATP]/[ADP] concentration ratio leads to closure of ATP-sensitive K+ channels (K-ATP), membrane depolarization, and influx of Ca2+ through voltage-dependent Ca2+ channels (VDCCs). Ca2+ influx stimulates exocytosis of secretory granules by promoting their fusion with
the plasma membrane. Under conditions where Ca2+ release channels are sensitized by GLP-1, Ca2+ influx also stimulates CICR, generating an additional round of ATP production and
K-ATP channel closure. In the absence of glucose, no ”fuel” is available to support
ATP production, and GLP-1 fails to stimulate insulin secretion. This new ”feed-forward”
hypothesis of β-cell stimulus-secretion coupling may provide a mechanistic explanation
as to how GLP-1 exerts a beneficial blood glucose-lowering effect in type 2 diabetic
subjects.
Key words
Glucose · GLP-1 · cAMP · PKA · Epac · Insulin secretion
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G. G. Holz, Ph. D.
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