Loss of connexin36 channels alters beta-cell coupling, islet synchronization of glucose-induced Ca2+ and insulin oscillations, and basal insulin release.
Normal insulin secretion requires the coordinated functioning of beta-cells within pancreatic islets. This coordination depends on a communications network that involves the interaction of beta-cells with extracellular signals and neighboring cells. In particular, adjacent beta-cells are coupled via channels made of connexin36 (Cx36). To assess the function of this protein, we investigated islets of transgenic mice in which the Cx36 gene was disrupted by homologous recombination. We observed that compared with wild-type and heterozygous littermates that expressed Cx36 and behaved as nontransgenic controls, mice homozygous for the Cx36 deletion (Cx36(-/-)) featured beta-cells devoid of gap junctions and failing to exchange microinjected Lucifer yellow. During glucose stimulation, islets of Cx36(-/-) mice did not display the regular oscillations of intracellular calcium concentrations ([Ca(2+)](i)) seen in controls due to the loss of cell-to-cell synchronization of [Ca(2+)](i) changes. The same islets did not release insulin in a pulsatile fashion, even though the overall output of the hormone in response to glucose stimulation was normal. However, under nonstimulatory conditions, islets lacking Cx36 showed increased basal release of insulin. These data show that Cx36-dependent signaling is essential for the proper functioning of beta-cells, particularly for the pulsatility of [Ca(2+)](i) and insulin secretion during glucose stimulation.
Ravier
Magalie A
MA
Department of Cell Physiology and Metabolism, University of Geneva, C.M.U., 1 rue Michel Servet, 1211 Geneva 4, Switzerland.
Güldenagel
Martin
M
Charollais
Anne
A
Gjinovci
Asllan
A
Caille
Dorothée
D
Söhl
Goran
G
Wollheim
Claes B
CB
Willecke
Klaus
K
Henquin
Jean-Claude
JC
Meda
Paolo
P
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D017630:Connexins / Q000235:genetics / Q000502:physiology*; D005260:Female; D005947:Glucose / Q000502:physiology*; D006579:Heterozygote; D006720:Homozygote; D007328:Insulin / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000097004:Gap Junction delta-2 Protein
D002118:Calcium; D017630:Connexins; D005947:Glucose; D007328:Insulin; D000097004:Gap Junction delta-2 Protein