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To ATP or Not To ATP: This Is the Question

A. Accardi

Published 2008 in The Journal of General Physiology

ABSTRACT

Correspondence to Alessio Accardi: a l e s s i o a c c a r d i @ u i o w a . e d u The ability to sense the metabolic state of a cell and tune its electrical activity through the direct or indirect modulation of ion transport systems by ATP is essential in a multitude of physiological processes in both excitable and nonexcitable cells. For example in pancreatic cells an increase in the ATP levels induces closure of the K ATP channels, leading to depolarization of the membrane, triggering insulin secretion (Ashcroft, 2006), and the energy derived from ATP hydrolysis is used to drive inward nutrient movement or outward xenobiotic transport ( Davidson and Maloney, 2007 ). The structural motifs regulating ATP binding and hydrolysis have been elucidated in atomic detail by the resolution of numerous crystal structures, both of isolated domains and of complete proteins ( Walker et al., 1982 ; Hollenstein et al., 2007 ). Members of the CLC family of Cl channels and transporters have only been peripherally involved in ATP-sensing processes. The cytoplasmic domains of all eukaryotic CLCs contain two cystathionine -synthase (CBS) domains homologous to those found in a wide variety of other systems ( Scott et al., 2004 ). In several cases it has been shown that these domains mediate direct binding of and regulate modulation of their host proteins by adenosine ligands, and it has been proposed that CLC function might also be regulated by ATP ( Scott et al., 2004 ). However the reports offered indirect evidence: ATP and its derivatives could prevent rundown of CLC-4 currents ( Vanoye and George, 2002 ), and disease-causing mutations in the cytoplasmic domains of CLC-1 and CLC-2 led to changes in the ATPbinding properties of their isolated CBS domains ( Scott et al., 2004 ; Wellhauser et al., 2006 ). The pathophysiological relevance of these domains in CLC-mediated Cl transport is highlighted by the numerous mutations localizing within their boundaries that compromise protein function and cause a number of genetically inherited disorders such as myotonia, Bartter syndrome, osteopetrosis, Dent ’ s disease, and epilepsy ( Jentsch et al., 2005 ; Ignoul and Eggermont, 2005 ). Functionally these domains have been implicated in regulating channel gating (Est é vez et al., 2004; Bykova et al., 2006 ), but as to how they are involved, we do not know. Channel opening in CLC-1 is regulated by two distinct and inter-

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