Multisite phosphorylation of the cardiac ryanodine receptor: a random or coordinated event?
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Multisite phosphorylation of the cardiac ryanodine receptor: a random or coordinated event? Jana Gaburjakova 1 & Eva Krejciova 1 & Marta Gaburjakova 1 Received: 9 July 2020 / Revised: 3 September 2020 / Accepted: 2 October 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Many proteins are phosphorylated at more than one phosphorylation site to achieve precise tuning of protein function and/or integrate a multitude of signals into the activity of one protein. Increasing the number of phosphorylation sites significantly broadens the complexity of molecular mechanisms involved in processing multiple phosphorylation sites by one or more distinct kinases. The cardiac ryanodine receptor (RYR2) is a well-established multiple phospho-target of kinases activated in response to β-adrenergic stimulation because this Ca2+ channel is a critical component of Ca2+ handling machinery which is responsible for β-adrenergic enhancement of cardiac contractility. Our review presents a selective overview of the extensive, often conflicting, literature which focuses on identifying reliable lines of evidence to establish if multiple RYR2 phosphorylation is achieved randomly or in a specific sequence, and whether phosphorylation at individual sites is functionally specific and additive or similar and can therefore be substituted. Keywords Cardiac muscle . Ryanodine receptor . Phosphorylation . Protein kinase A . CaM kinase
Introduction It is generally recognized that the performance of the heart is regulated by two intricate interacting components of the autonomic nervous system, the sympathetic and parasympathetic. The sympathetic nervous system plays a central role in increasing cardiac output when required as occurs in exercise and the fight-or-flight response. The binding of sympathetic transmitters to β-adrenergic receptors in the heart generates cAMP which directly activates cAMP-dependent protein kinase (PKA) and leads to strong phosphorylation of several proteins involved in Ca2+ handling and contractile machineries in order to enhance Ca2+ signaling and thus cardiac contractility. These proteins include phospholamban (PLB), the ryanodine receptor (RYR2), the L-type Ca2+ channel, and troponin I (TnI) (reviewed in [8]). In contrast, the parasympathetic nervous system acts through reducing cardiac activity and is most active under restful conditions. Parasympathetic
* Marta Gaburjakova [email protected] 1
Institute of Molecular Physiology and Genetics, Centre of Biosciences, Slovak Academy of Sciences, Dubravska cesta 9, 840 05 Bratislava, Slovak Republic
transmitters, after binding to muscarinic receptors in the heart, initiate a signaling cascade distinct from the cAMP pathway. Muscarinic stimulation involves cGMP synthesis which results in activation of several targets, such as cGMPdependent protein kinase (PKG). In the absence of sympathetic activity, PKG phosphorylates at least three known PKA protein substrates, including the RYR2 channel [6, 44], the L-type Ca 2+ channel [71
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