Regulation of protein kinases and coregulatory interplay of S-100beta and serotonin transporter on serotonin levels in diabetic rat brain

• Published in: Journal of neuroscience research 2009-01, Vol.87 (1), p.246
• Main Authors: Ramakrishnan, R, Sheeladevi, R, Namasivayam, A
• Format: Article
• Language: English
• Subjects: Acetoacetates - blood; Alloxan; Analysis of Variance; Animals; Blood Glucose; Brain - metabolism; Carbonates - blood; Diabetes Mellitus - chemically induced; Diabetes Mellitus - pathology; Disease Models, Animal; Gene Expression Regulation, Enzymologic - drug effects; Gene Expression Regulation, Enzymologic - physiology; Hydrogen-Ion Concentration; Male; Nerve Growth Factors - metabolism; Protein Kinases - classification; Protein Kinases - metabolism; Rats; Rats, Wistar; S100 Calcium Binding Protein beta Subunit; S100 Proteins - metabolism; Serotonin - metabolism; Serotonin Plasma Membrane Transport Proteins - metabolism; Time Factors
• ISSN: 1097-4547
• DOI: 10.1002/jnr.21833

Protein kinases are critical component in the regulation of signal transduction pathways, including neurotransmitters. Our previous studies have shown that serotonin (5-HT) altered under diabetic condition was accompanied by alterations of protein kinase C-alpha (PKC-alpha) and CaMKII, and those alterations were reversed after insulin administration. The current study showed that alloxan-induced diabetic animals revealed hyperglycemia and was associated with an increase in the content of 5-HT, PKC-alpha expression and PKC activity (P < 0.05) simultaneously in striatum (ST), midbrain (MB), pons medulla (PM), cerebellum (CB), and cerebral cortex (CCX) from 7 days to 60 days. Although the 5-HT levels in hippocampus (HC) and hypothalamus (HT) were not altered, the PKC-alpha expression and PKC activity showed increases (P < 0.05) in level in HC. Insulin administration reversed all these changes to a normal level. In contrast, the in vitro study has shown that the 5-HT levels correlated with PKC-alpha expressions as well as PKC activity (P < 0.05) only in ST, MB, and CB either after induction with phorbol 12-myristate 13-acetate (PMA) or blocking with chelerythrine, whereas PM and CCX remained elevated (P < 0.05), implying a regulatory role for PKC-alpha only in ST, MB, and CB. However, our consecutive studies have shown that the 5-HT level in PM was regulated by p38-mitogen-activated protein kinase (p38-MAPK) both in vivo and in vitro, whereas the 5-HT level in CCX was coregulated by S-100beta by protein-protein interaction with serotonin transporter (SERT) via 8-bromoadenosine 3',5'-cyclic monophosphate sodium salt (8-Br-cAMP)-induced cAMP/PKAII pathway(s).