Adenosine receptor subtypes modulate two major functional pathways for hippocampal serotonin release.
To clarify the mechanisms of interaction between adenosine A(1) receptor (A1-R) and adenosine A(2) receptor (A2-R) on neurotransmitter release, this study determined the functional interactions among adenosine receptors (AD-Rs), voltage-sensitive Ca(2+) channels (VSCCs), protein kinases (PKs), and synaptic proteins [N-ethylmaleimide-sensitive factor (NSF) attachment protein (SNAP) receptors] on hippocampal serotonin release using in vivo microdialysis in freely moving rat. Basal serotonin release was regulated by two functional complexes: N-type VSCC (N-VSCC)/calcium-phospholipid-dependent protein kinase (PKC)/syntaxin (major pathway) and P-type VSCC (P-VSCC)/cyclic AMP-dependent protein kinase (PKA)/synaptobrevin (minor pathway). However, K(+)-evoked serotonin release was regulated by N-VSCC/PKC/syntaxin (minor pathway) and P-VSCC/PKA/synaptobrevin (major pathway). A1-R antagonists increased basal serotonin release, which was reduced by inhibitors of N-VSCC, PKC, and syntaxin predominantly and by inhibitors of PKA and synaptobrevin weakly, but was not affected by P-VSCC inhibitor. In the presence of A1-R antagonist, A2-R agonists increased basal serotonin release, which was inhibited by inhibitors of P-VSCC, PKA, and synaptobrevin predominantly and reduced by inhibitors of N-VSCC, PKC, and syntaxin weakly. Under the condition of activation of adenylate cyclase in the absence of A1-R antagonists, A2-R agonists increased basal serotonin release. A1-R antagonist and A2-R agonist enhanced K(+)-evoked serotonin release, which was inhibited by inhibitors of P-VSCC, PKA, and synaptobrevin predominantly. These results suggest that an activation of A1-R suppresses serotonin release via inhibition of both N-VSCC/PKC/syntaxin and P-VSCC/PKA/synaptobrevin pathways, and an activation of A2-R stimulates serotonin release via enhancement of the P-VSCC/PKA/synaptobrevin pathway. Therefore, PKA activity plays an important role in the interaction between A1-R and A2-R on hippocampal serotonin release.
Okada
M
M
Department of Neuropsychiatry, Hirosaki University, Hirosaki 036-8216, Japan. okadamot@cc.hirosaki-u.ac.jp
Nutt
D J
DJ
Murakami
T
T
Zhu
G
G
Kamata
A
A
Kawata
Y
Y
Kaneko
S
S
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D017551:Microdialysis; D011188:Potassium / Q000378:metabolism / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D050765:Qa-SNARE Proteins; D050683:R-SNARE Proteins; D051381:Rats; D017208:Rats, Wistar; D018047:Receptors, Purinergic P1 / Q000378:metabolism*; D050600:SNARE Proteins; D012701:Serotonin / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D033921:Vesicular Transport Proteins; D014851:Wakefulness
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D050765:Qa-SNARE Proteins; D050683:R-SNARE Proteins; D018047:Receptors, Purinergic P1; D050600:SNARE Proteins; D033921:Vesicular Transport Proteins; D012701:Serotonin; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D000262:Adenylyl Cyclases; D011188:Potassium