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J. Biol. Chem., Vol. 282, Issue 4, 2656-2665, January 26, 2007

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

From the Department of Experimental Medicine (DIMES), Biochemistry Section, and Centre of Excellence for Biomedical Research (CEBR), University of Genoa, Viale Benedetto XV, 1-16132 Genoa, Italy

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.

Received for publication, July 20, 2006 , and in revised form, November 28, 2006.

^* This work was supported in part by grants from the Ministero dell'lstruzione, dell'Università e della Ricerca, Fondo per gli Investimenti della Ricerca di Base, and Progetti di Rilevante Interesse Nazionale, and from the University of Genoa. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: University of Genoa, DIMES–Biochemistry Section, Viale Benedetto XV, 1-16132 Genoa. Tel.: 39-010-3538162; Fax: 39-010-518343; E-mail: pontremoli{at}unige.it.

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