Glucagon-like peptide-1-(7-36)amide and a rise in cyclic adenosine 3',5'-monophosphate increase cytosolic free Ca2+ in rat pancreatic beta-cells by enhancing Ca2+ channel activity.
Glucagon-like peptide-1 (GLP-1), in the form of either GLP-1-(7-36)amide or GLP-1-(7-37), has been shown to potently stimulate insulin release in a glucose-dependent manner and is suggested to be a physiological incretin. To explore the mechanisms by which GLP-1-(7-36)amide stimulates insulin release, we investigated its action on the cytosolic free Ca2+ concentration ([Ca2+]i) in single rat pancreatic beta-cells by the dual wavelength microfluorometry with fura-2. In the presence of 8.3 mM glucose, GLP-1-(7-36)amide at a concentration as low as 3 x 10(-12) M produced a rapid transient increase in [Ca2+]i in some of the single beta-cells. GLP-1-(7-36)amide at 10(-11) M or more evoked the [Ca2+]i response in the majority of beta-cells. In the presence of 2.8 mM glucose, GLP-1-(7-36)amide was without effect. The [Ca2+]i response to GLP-1-(7-36)amide was completely and reversibly inhibited under Ca(2+)-free conditions and by 1 microM nitrendipine, a blocker of L-type Ca2+ channels. Elevation of cAMP in beta-cells by either 10 microM forskolin, an activator of adenylyl cyclase, or 5 mM (bu)2cAMP (db-cAMP) produced an increase in [Ca2+]i similar to that caused by GLP-1-(7-36)amide. The db-cAMP-induced increase in [Ca2+]i was also completely blocked by nitrendipine. In the continuous presence of GLP-1-(7-36)amide and after the transient [Ca2+]i increase it elicited, db-cAMP failed to evoke the [Ca2+]i response. It is concluded that GLP-1-(7-36)amide at physiological concentrations and a rise in cAMP increase [Ca2+]i in pancreatic beta-cells by enhancing the activity of L-type Ca2+ channels in the beta-cell plasma membrane. It is suggested that the cAMP-operative mechanism is involved in the GLP-1-(7-36)amide action to increase [Ca2+]i in beta-cells.
Yada
T
T
Department of Physiology, Kagoshima University School of Medicine, Japan.
Itoh
K
K
Nakata
M
M
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism / Q000494:pharmacology*; D003600:Cytosol / Q000378:metabolism*; D005934:Glucagon / Q000378:metabolism; D052216:Glucagon-Like Peptide 1; D004763:Glucagon-Like Peptides; D005947:Glucose / Q000494:pharmacology; D007515:Islets of Langerhans / Q000378:metabolism*; D009568:Nitrendipine / Q000494:pharmacology; D009994:Osmolar Concentration; D010446:Peptide Fragments / Q000378:metabolism*; D051381:Rats
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D010446:Peptide Fragments; C055453:glucagon-like peptide 1 (7-36)amide; D004763:Glucagon-Like Peptides; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D009568:Nitrendipine; D000242:Cyclic AMP; D005947:Glucose; D002118:Calcium