Metabotropic glutamate receptor type 4 is involved in autoinhibitory cascade for glucagon secretion by alpha-cells of islet of Langerhans.
In islets of Langerhans, L-glutamate is stored in glucagon-containing secretory granules of alpha-cells and cosecreted with glucagon under low-glucose conditions. The L-glutamate triggers secretion of gamma-aminobutyric acid (GABA) from beta-cells, which in turn inhibits glucagon secretion from alpha-cells through the GABAA receptor. In the present study, we tested the working hypothesis that L-glutamate functions as an autocrine/paracrine modulator and inhibits glucagon secretion through a glutamate receptor(s) on alpha-cells. The addition of L-glutamate at 1 mmol/l; (R,S)-phosphonophenylglycine (PPG) and (S)-3,4-dicarboxyphenylglycine (DCPG), specific agonists for class III metabotropic glutamate receptor (mGluR), at 100 micromol/l; and (1S,3R,4S)-1-aminocyclopentane-1,3,4-tricarboxylic acid (ACPT-I) at 50 micromol/l inhibited the low-glucose-evoked glucagon secretion by 87, 81, 73, and 87%, respectively. This inhibition was dose dependent and was blocked by (R,S)-cyclopropyl-4-phosphonophenylglycine (CPPG), a specific antagonist of class III mGluR. Agonists of other glutamate receptors, including kainate and quisqualate, had little effectiveness. RT-PCR and immunological analyses indicated that mGluR4, a class III mGluR, was expressed and localized with alpha- and F cells, whereas no evidence for expression of other mGluRs, including mGluR8, was obtained. L-Glutamate, PPG, and ACPT-I decreased the cAMP content in isolated islets, which was blocked by CPPG. Dibutylyl-cAMP, a nonhydrolyzable cAMP analog, caused the recovery of secretion of glucagon. Pertussis toxin, which uncouples adenylate cyclase and inhibitory G-protein, caused the recovery of both the cAMP content and secretion of glucagon. These results indicate that alpha- and F cells express functional mGluR4, and its stimulation inhibits secretion of glucagon through an inhibitory cAMP cascade. Thus, L-glutamate may directly interact with alpha-cells and inhibit glucagon secretion.
Uehara
Shunsuke
S
Department of Biochemistry, Faculty of Pharmaceutical Sciences, Okayama University, Okayama, Japan.
Muroyama
Akiko
A
Echigo
Noriko
N
Morimoto
Riyo
R
Otsuka
Masato
M
Yatsushiro
Shouki
S
Moriyama
Yoshinori
Y
D000818:Animals; D003517:Cyclopentanes / Q000494:pharmacology*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D020869:Gene Expression Profiling; D005934:Glucagon / Q000378:metabolism*; D005947:Glucose / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D037342:Pertussis Toxin / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000502:physiology*; D014233:Tricarboxylic Acids / Q000494:pharmacology*
C409063:1-aminocyclopentane-1,2,4-tricarboxylic acid; D003517:Cyclopentanes; D018690:Excitatory Amino Acid Agonists; D018094:Receptors, Metabotropic Glutamate; D014233:Tricarboxylic Acids; C102718:metabotropic glutamate receptor 3; D018698:Glutamic Acid; D005934:Glucagon; D037342:Pertussis Toxin; D005947:Glucose; C108823:metabotropic glutamate receptor 4