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      Alterations in reversible protein histidine phosphorylation as intracellular signals in cardiovascular disease

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          Reversible phosphorylation of amino acid side chains in proteins is a frequently used mechanism in cellular signal transduction and alterations of such phosphorylation patterns are very common in cardiovascular diseases. They reflect changes in the activities of the protein kinases and phosphatases involving signaling pathways. Phosphorylation of serine, threonine, and tyrosine residues has been extensively investigated in vertebrates, whereas reversible histidine phosphorylation, a well-known regulatory signal in lower organisms, has been largely neglected as it has been generally assumed that histidine phosphorylation is of minor importance in vertebrates. More recently, it has become evident that the nucleoside diphosphate kinase isoform B (NDPK-B), an ubiquitously expressed enzyme involved in nucleotide metabolism, and a highly specific phosphohistidine phosphatase (PHP) form a regulatory histidine protein kinase/phosphatase system in mammals. At least three well defined substrates of NDPK-B are known: The β-subunit of heterotrimeric G-proteins (Gβ), the intermediate conductance potassium channel SK4 and the Ca 2+ conducting TRP channel family member, TRPV5. In each of these proteins the phosphorylation of a specific histidine residue regulates cellular signal transduction or channel activity. This article will therefore summarize our current knowledge on protein histidine phosphorylation and highlight its relevance for cardiovascular physiology and pathophysiology.

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          Most cited references 90

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          Inflammation in atherosclerosis.

           Peter Libby (2015)
          Abundant data link hypercholesterolaemia to atherogenesis. However, only recently have we appreciated that inflammatory mechanisms couple dyslipidaemia to atheroma formation. Leukocyte recruitment and expression of pro-inflammatory cytokines characterize early atherogenesis, and malfunction of inflammatory mediators mutes atheroma formation in mice. Moreover, inflammatory pathways promote thrombosis, a late and dreaded complication of atherosclerosis responsible for myocardial infarctions and most strokes. The new appreciation of the role of inflammation in atherosclerosis provides a mechanistic framework for understanding the clinical benefits of lipid-lowering therapies. Identifying the triggers for inflammation and unravelling the details of inflammatory pathways may eventually furnish new therapeutic targets.
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            Mechanism of calcium gating in small-conductance calcium-activated potassium channels.

            The slow afterhyperpolarization that follows an action potential is generated by the activation of small-conductance calcium-activated potassium channels (SK channels). The slow afterhyperpolarization limits the firing frequency of repetitive action potentials (spike-frequency adaptation) and is essential for normal neurotransmission. SK channels are voltage-independent and activated by submicromolar concentrations of intracellular calcium. They are high-affinity calcium sensors that transduce fluctuations in intracellular calcium concentrations into changes in membrane potential. Here we study the mechanism of calcium gating and find that SK channels are not gated by calcium binding directly to the channel alpha-subunits. Instead, the functional SK channels are heteromeric complexes with calmodulin, which is constitutively associated with the alpha-subunits in a calcium-independent manner. Our data support a model in which calcium gating of SK channels is mediated by binding of calcium to calmodulin and subsequent conformational alterations in the channel protein.
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              Small-conductance Ca2+-activated K+ channels: form and function.

              Small-conductance Ca(2+)-activated K(+) channels (SK channels) are widely expressed throughout the central nervous system. These channels are activated solely by increases in intracellular Ca(2+). SK channels are stable macromolecular complexes of the ion pore-forming subunits with calmodulin, which serves as the intrinsic Ca(2+) gating subunit, as well as with protein kinase CK2 and protein phosphatase 2A, which modulate Ca(2+) sensitivity. Well-known for their roles in regulating somatic excitability in central neurons, SK channels are also expressed in the postsynaptic membrane of glutamatergic synapses, where their activation and regulated trafficking modulate synaptic transmission and the induction and expression of synaptic plasticity, thereby affecting learning and memory. In this review we discuss the molecular and functional properties of SK channels and their physiological roles in central neurons.

                Author and article information

                1Institute for Experimental and Clinical Pharmacology and Toxicology, Mannheim Medical Faculty, Heidelberg University , Mannheim, Germany
                2School of Chemistry and Biochemistry, The University of Western Australia , Crawley, Australia
                Author notes

                Edited by: Friederike Cuello, University Medical Center Hamburg-Eppendorf, Germany

                Reviewed by: Gaetano Santulli, Columbia University, USA; Robert Gros, Robarts Research Institute, Canada; Andrew Snabaitis, Kingston University London, UK

                *Correspondence: Thomas Wieland, Institute for Experimental and Clinical Pharmacology and Toxicology, Mannheim Medical Faculty, Heidelberg University, Maybachstrasse 14, 68169 Mannheim, Germany, thomas.wieland@

                This article was submitted to Cardiovascular and Smooth Muscle Pharmacology, a section of the journal Frontiers in Pharmacology.

                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                21 August 2015
                : 6
                4543942 10.3389/fphar.2015.00173
                Copyright © 2015 Wieland and Attwood.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Figures: 2, Tables: 0, Equations: 0, References: 89, Pages: 9, Words: 7018
                Funded by: Deutsche Forschungsgemeinschaft 10.13039/501100001659
                Award ID: Wi 1373/9-3, SFB TR23, TP B6, GRK 1874 SP2
                Funded by: Bundesministerium für Bildung und Forschung 10.13039/501100002347
                Funded by: European Foundation for the Study of Diabetes 10.13039/501100001648
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