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J. Biol. Chem., Vol. 279, Issue 39, 40494-40504, September 24, 2004

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Sustained Entry of Ca²⁺ Is Required to Activate Ca²⁺-Calmodulin-dependent Phosphodiesterase 1A^*

Tasmina A. Goraya, Nanako Masada, Antonio Ciruela, and Dermot M. F. Cooper

From the Department of Pharmacology, University of Cambridge, Tennis Court Rd., Cambridge, CB2 1PD, United Kingdom

Regulation of adenylyl cyclases (ACs) by Ca²⁺ requires capacitative Ca²⁺ entry (CCE) (Cooper, D. M. F. (2003) Biochem. J. 375, 517–529), but whether Ca²⁺-sensitive phosphodiesterases (PDEs) are similarly discriminating has never been addressed. In the present study, a variety of conditions were devised to manipulate [Ca²⁺]_i so that we could ask whether PDE1 selectively responds to different modes of elevating [Ca²⁺]_i, viz. Ca²⁺ released from intracellular stores and various modes of Ca²⁺ entry. In 1321N1 human astrocytoma cells, the endogenous PDE1 (identified as PDE1A by reverse transcriptase-PCR) was largely insensitive to Ca²⁺ released from carbachol-sensitive stores but was robustly stimulated by a similar rise in [Ca²⁺]_i due to carbachol-induced Ca²⁺ influx. Gd³+, which effectively blocked thapsigargin-induced CCE and its effect on PDE1A, also inhibited the activation of PDE1A by carbachol-induced Ca²⁺ entry. However, non-selective ionomycin-mediated Ca²⁺ entry also activated PDE1A, so that, unlike Ca²⁺-sensitive ACs, PDE1A cannot discriminate between the different sources of Ca²⁺ entry. Fractionation of the cells revealed that the Ca²⁺-calmodulin-stimulated PDE activity was not present at the plasma membrane but was associated with the cytosol and the organellar compartments of the cell. Therefore, the apparent disparity between PDE1A and ACs is likely to be the consequence of their differential subcellular localization. Nevertheless, in a physiological context, where artificial modes of elevating [Ca²⁺]_i are not available, as with ACs, a dependence on CCE would be evident, and it would be the duration of this influx of Ca²⁺ that would determine how long PDE1A was activated.

Received for publication, December 9, 2003 , and in revised form, July 20, 2004.

^* The work was supported by the Wellcome Trust and the National Institutes of Health. 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.

To whom correspondence should be addressed. Tel.: 44-1223-334-063; Fax: 44-1223-334-040; E-mail: dmfc2{at}cam.ac.uk.

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