CYCLIC adenosine 3',5'-monophosphate potentiates Ca2+ signaling and insulin secretion by phospholipase C-linked hormones in HIT cells.
Neurotransmitters and hormones, by binding to receptors linked to adenylate cyclase or phospholipase C (PLC), increase cytosolic free Ca2+ and potentiate glucose-induced insulin release from beta-cells. Interactions between both signaling pathways may occur and be of relevance to the regulation of insulin secretion. We demonstrate here that in single insulin-secreting HIT cells, forskolin and 8-bromo-cAMP, which stimulate Ca2+ influx through voltage-dependent Ca2+ channels (VDCC), cause a marked increase in the frequency, amplitude, and duration of Ca2+ transients evoked by hormones linked to PLC, such as arginine vasopressin (AVP) or bombesin. Forskolin also potentiates AVP- or bombesin-induced insulin secretion from populations of HIT cells in the presence of elevated glucose (10 mM). BAY K 8644, an activator of VDCC, mimicked the effects of elevated cAMP on both AVP- and bombesin-induced Ca2+ transients and insulin release, which suggests that enhanced Ca2+ influx through VDCC activated by cAMP-dependent mechanisms underlies the positive interactions of both signaling pathways on Ca2+ signaling and insulin secretion. Physiologically, synergistic cross-signaling between the cAMP- and Ca2+ -phosphoinositide signaling pathway could be important for the regulation of insulin release under conditions where extracellular glucose is high and beta-cells are exposed to multiple stimuli activating adenylate cyclase or PLC at the same time.
Schöfl
C
C
Abteilung Klinische Endokrinologie, Medizinische Hochschule Hannover, Germany.
Rossig
L
L
Mader
T
T
von zur Mühlen
A
A
Brabant
G
G
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology*; D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology; D001839:Bombesin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology*; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism*; D004533:Egtazic Acid / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000502:physiology*; D007700:Kinetics; D008647:Mesocricetus; D009543:Nifedipine / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013729:Terpenes / Q000494:pharmacology; D019284:Thapsigargin; D013997:Time Factors
D004791:Enzyme Inhibitors; D007328:Insulin; D013729:Terpenes; D001127:Arginine Vasopressin; D005576:Colforsin; D015124:8-Bromo Cyclic Adenosine Monophosphate; D004533:Egtazic Acid; D019284:Thapsigargin; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D000242:Cyclic AMP; D000252:Calcium-Transporting ATPases; D009543:Nifedipine; D001839:Bombesin; D002118:Calcium