Regulation of Calpain Activity in Rat Brain with Altered Ca2+ Homeostasis

• Published in: The Journal of biological chemistry 2007-01, Vol.282 (4), p.2656-2665
• Main Authors: Averna, Monica, Stifanese, Roberto, De Tullio, Roberta, Passalacqua, Mario, Defranchi, Enrico, Salamino, Franca, Melloni, Edon, Pontremoli, Sandro
• Format: Article
• Language: English
• Subjects: Animals; Blood Pressure - drug effects; Brain - metabolism; Calcium - metabolism; Calcium-Transporting ATPases - antagonists & inhibitors; Calcium-Transporting ATPases - metabolism; Calpain - metabolism; Diet; Down-Regulation; Homeostasis; Humans; Hypertension - metabolism; Hypertension - physiopathology; Male; Rats; Rats, Inbred Strains; Sodium Chloride, Dietary - administration & dosage
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M606919200

Activation of calpain occurs as an early event in correlation with an increase in [Ca2+]i induced in rat brain upon treatment with a high salt diet for a prolonged period of time. The resulting sequential events have been monitored in the brain of normal and hypertensive rats of the Milan strain, diverging for a constitutive alteration in the level of [Ca2+]i found to be present in nerve cells of hypertensive animals. After 2 weeks of treatment, the levels of the plasma membrane Ca2+-ATPase and of native calpastatin are profoundly decreased. These degradative processes, more pronounced in the brain of hypertensive rats, are progressively and efficiently compensated in the brain of both rat strains by different incoming mechanisms. Along with calpastatin degradation, 15-kDa still-active inhibitory fragments are accumulated, capable of efficiently replacing the loss of native inhibitor molecules. A partial return to a more efficient control of Ca2+ homeostasis occurs in parallel, assured by an early increase in the expression of Ca2+-ATPase and of calpastatin, both producing, after 12 weeks of a high salt (sodium) diet, the restoration of almost original levels of the Ca2+ pump and of significant amounts of native inhibitor molecules. Thus, conservative calpastatin fragmentation, associated with an increased expression of Ca2+-ATPase and of the calpain natural inhibitor, has been demonstrated to occur in vivo in rat brain. This represents a sequential adaptive response capable of overcoming the effects of calpain activation induced by a moderate long term elevation of [Ca2+]i.