Ca2+-handling proteins and heart failure: Novel molecular targets?

Prestle, J., Quinn, F. and Smith, G. (2003) Ca2+-handling proteins and heart failure: Novel molecular targets? Current Medicinal Chemistry, 10(11), pp. 967-981.

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Calcium (Ca2+) ions are the currency of heart muscle activity. During excitation-contraction coupling Ca2+ is rapidly cycled between the cytosol (where it activates the myofilaments) and the sarcoplasmic reticulum (SR), the Ca2+ store. These fluxes occur by the transient activity of Ca2+-pumps and -channels. In the failing human heart, changes in activity and expression profile of Ca2+-handling proteins, in particular the SR Ca2+-ATPase (SERCA2a), are thought to cause an overall reduction in the amount of SR-Ca2+ available for contraction. In the steady state, the Ca2+-content of the SR is essentially a balance between Ca2+-uptake via SERCA2a pump and Ca2+-release via the cardiac SR Ca2+-release channel complex (Ryanodine receptor, RyR2). This review discusses current pharmacological options available to enhance cardiac SR Ca2+ content and the implications of this approach as an inotropic therapy in heart failure. Two options are considered: (i) activation of the SERCA2a pump to increase SR Ca2+-uptake, and (ii) reduction of SR Ca2+-leakage through RyR2. RyR2 forms a macromolecular complex with a number of regulatory proteins that either remain permanently bound or that interact in a time- and/or Ca2+-dependant manner. These regulatory proteins can dramatically affect RyR2 function, e.g. over-expression of the accessory protein FK 506-binding protein 12.6 (FKBP12.6) has recently been shown to reduce SR Ca2+-leak. Recent attempts to design positive inotropes for chronic administrations have focussed on the use of phosphodiesterase III inhibitors (PDE III inhibitors). These compounds, which increase intracellular cAMP-levels, have failed in clinical trials. Therefore medical researchers are seeking new drugs that act through alternative pathways. Novel cardiac inotropes targeting SR Ca2+-cycling proteins may have the potential to fill this gap.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Smith, Professor Godfrey
Authors: Prestle, J., Quinn, F., and Smith, G.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
College of Medical Veterinary and Life Sciences
Journal Name:Current Medicinal Chemistry
Publisher:Bentham Science Publishers Ltd.

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