Recognition and Activation of Ryanodine Receptors by Purines

Author(s): Armando Butanda-Ochoa, Germund Hojer, Veronica Morales-Tlalpan, Mauricio Diaz-Munoz.

Journal Name: Current Medicinal Chemistry

Volume 13 , Issue 6 , 2006

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Abstract:

Ryanodine receptor (RyR) is a tetrameric, high molecular weight protein that functions as a calcium release channel. It plays a key role in phenomena such as signal transduction, excitation-contraction and excitation-secretion coupling. Hyperthermia maligna, central core disease and myocardial infarction have been related with RyR dysfunction. RyR is present as three isoforms in vertebrates: RyR 1 mainly localized in skeletal muscle, RyR 2 in cardiac muscle, and RyR 3 in nervous system. RyR is regulated by a number of physiological and pharmacological factors. Main physiological modulators: calcium, kinases and phosphatases, redox state and energy charge. Main pharmacological regulators: caffeine, dantrolene, ruthenium red, heavy metals and ryanodine. Purines have to do with both, physiological and pharmacological regulation of the RyR activity. So far, the mechanisms of RyR activation by ATP and caffeine have been described in detail using [3H]-ryanodine binding assays and unitary channel activity recorded in planar lipid bilayers. However, some questions remain to be addressed and are at present aim of active scrutiny: How many sites for purines are present in the RyR? Is the same site recognized by nucleotides and methylxanthines? What differences exist among the interaction between RyR and purine bases, nucleosides and nucleotides? Are the phosphate groups important for the recognition of nucleotides? Is the sugar moiety important for the recognition of nucleosides? The review article will examine the most recent specialized literature about the mechanism of activation of RyR by purines with emphasis on reports with approaches of structure-function and structure-activation.

Keywords: Ryanodine receptor, intracellular calcium dynamics, QSAR, CoMFA, dipolar moment vector, purines, ATP, adenosine

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Article Details

VOLUME: 13
ISSUE: 6
Year: 2006
Page: [647 - 657]
Pages: 11
DOI: 10.2174/092986706776055715
Price: $58