L-triiodothyronine differentially and nongenomically regulates synaptosomal protein phosphorylation in adult rat brain cerebral cortex: role of calcium and calmodulin.
Adult-onset thyroid disorders in humans impair several important central nervous system functions, causing various neuropsychiatric diseases. However, the mechanisms of thyroid hormone (TH) action in the mature mammalian brain remain unclear. Recent nongenomic actions of TH in adult brains are spotlighted. Many nongenomic mechanisms are modulated by phosphorylation-dephosphorylation of substrate proteins. In the present study, L-triiodothyronine (L-T3) demonstrated differential regulation of phosphorylation status of five different synaptosomal proteins (63, 53, 38, 23, and 16 kD) in both a Ca(2+)/calmodulin (CaM)-dependent and -independent manner. L-T3 increased the level of phosphorylation of all these five proteins. Ca(2+)/CaM further stimulated phosphorylation of 63- and 53-kD proteins by L-T3, which were inhibited both by EGTA (Ca(2+)-chelator) or KN62 (Ca(2+)/CaM kinase-II [CaMK-II] inhibitor), suggesting the role of CaMK-II. L-T3 increased the phosphorylation of 23- and 38-kD proteins; the effect was independent of EGTA or KN62. The presence of Ca(2+) decreased L-T3-induced phosphorylation of 63-, 53- and 38-kD proteins. Surprisingly, l-T3-induced phosphorylation of 16-kD protein was not augmented further with Ca(2+) or Ca(2+)/CaM; instead, the presence of CaM abolished the L-T3-induced phosphorylation. EGTA or KN62 could not restore the effect of CaM-induced dephosphorylation of this protein. This study identified the role of Ca(2+)/CaM in the regulation of L-T3-induced protein phosphorylation and supported a unique nongenomic mechanism of second messenger-mediated regulation of protein phosphorylation by TH in mature rat brain. This has profound implications for higher mental functions and strategies for novel therapeutics.
Sarkar
Pradip K
PK
Molecular Neuroendocrinology Laboratory, Department of Basic Science and Research, New York Chiropractic College, 2360 State Route 89, Seneca Falls, New York 13148, USA. psarkar@nycc.edu
D000818:Animals; D002118:Calcium / Q000502:physiology*; D002147:Calmodulin / Q000502:physiology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D066298:In Vitro Techniques; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*; D014284:Triiodothyronine / Q000494:pharmacology*
D002147:Calmodulin; D009419:Nerve Tissue Proteins; D014284:Triiodothyronine; D002118:Calcium