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

Wieland T, Attwood PV - Front Pharmacol (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Institute for Experimental and Clinical Pharmacology and Toxicology, Mannheim Medical Faculty, Heidelberg University , Mannheim, Germany.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

Molecular targets of NDPK-B and PHP and their proposed functions in physiology and pathophysiology. Three proteins, the cation channels SK4 and TRPV5 as well as the β-subunit of heterotrimeric G-proteins are substrates for NDPK-B-mediated phosphorylation on defined histidine residues (His). All three phosphohistidines are also substrates to dephosphorylation by PHP. Whereas the phosphorylation of classically regulates the open-probability of the channels, the phosphorylated G-protein β-subunit takes part in a phosphorelay activating heterotrimeric G-proteins. Apparently, by a complex formation with NDPK-C and caveolins (Cav), NDPK-B additionally contributes to caveolae formation and the composition of signaling complexes, e.g., G-protein-coupled receptor (GPCR) containing complexes, at the plasma membrane. Whereas the channels’ activities are linked to the indicated physiological and pathophysiological events, evidence for a contribution of the phosphorelay to the regulation of cardiac cAMP formation and thus contractility has been provided.
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Figure 2: Molecular targets of NDPK-B and PHP and their proposed functions in physiology and pathophysiology. Three proteins, the cation channels SK4 and TRPV5 as well as the β-subunit of heterotrimeric G-proteins are substrates for NDPK-B-mediated phosphorylation on defined histidine residues (His). All three phosphohistidines are also substrates to dephosphorylation by PHP. Whereas the phosphorylation of classically regulates the open-probability of the channels, the phosphorylated G-protein β-subunit takes part in a phosphorelay activating heterotrimeric G-proteins. Apparently, by a complex formation with NDPK-C and caveolins (Cav), NDPK-B additionally contributes to caveolae formation and the composition of signaling complexes, e.g., G-protein-coupled receptor (GPCR) containing complexes, at the plasma membrane. Whereas the channels’ activities are linked to the indicated physiological and pathophysiological events, evidence for a contribution of the phosphorelay to the regulation of cardiac cAMP formation and thus contractility has been provided.

Mentions: One of the first phosphoproteins to be identified that contained phosphohistidine was NDPK (Walinder, 1969a; Walinder et al., 1969). Walinder et al. (1969) showed that the phosphohistidine in NDPK was an intermediate in the phosphoryl transfer reaction between NTP and NDP catalyzed by the enzyme. More recently, it was discovered that NDPK can also act as a protein histidine kinase. NDPK-A was shown to phosphorylate a histidine residue in ATP-citrate-lyase (Wagner and Vu, 1995) whilst NDPK-B phosphorylates histidine residues in the β-subunit (Gβ) of heterotrimeric G-protein βγ-dimers (Gβγ; Cuello et al., 2003), the intermediate-conductance potassium-channel SK4 (encoded by the KCNN4 gene; Srivastava et al., 2006) and the Ca2+- conducting channel, TRPV5 (Cai et al., 2014) (Figure 2). As such, NDPKs are the best characterized mammalian histidine kinases, although little is known about the details of how they recognize their substrate proteins and catalyze the phosphoryl transfer reaction. Two of the protein substrates of NDPK-B, Gβ and SK4, play important roles in cardiovascular function and disease.


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

Wieland T, Attwood PV - Front Pharmacol (2015)

Molecular targets of NDPK-B and PHP and their proposed functions in physiology and pathophysiology. Three proteins, the cation channels SK4 and TRPV5 as well as the β-subunit of heterotrimeric G-proteins are substrates for NDPK-B-mediated phosphorylation on defined histidine residues (His). All three phosphohistidines are also substrates to dephosphorylation by PHP. Whereas the phosphorylation of classically regulates the open-probability of the channels, the phosphorylated G-protein β-subunit takes part in a phosphorelay activating heterotrimeric G-proteins. Apparently, by a complex formation with NDPK-C and caveolins (Cav), NDPK-B additionally contributes to caveolae formation and the composition of signaling complexes, e.g., G-protein-coupled receptor (GPCR) containing complexes, at the plasma membrane. Whereas the channels’ activities are linked to the indicated physiological and pathophysiological events, evidence for a contribution of the phosphorelay to the regulation of cardiac cAMP formation and thus contractility has been provided.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4543942&req=5

Figure 2: Molecular targets of NDPK-B and PHP and their proposed functions in physiology and pathophysiology. Three proteins, the cation channels SK4 and TRPV5 as well as the β-subunit of heterotrimeric G-proteins are substrates for NDPK-B-mediated phosphorylation on defined histidine residues (His). All three phosphohistidines are also substrates to dephosphorylation by PHP. Whereas the phosphorylation of classically regulates the open-probability of the channels, the phosphorylated G-protein β-subunit takes part in a phosphorelay activating heterotrimeric G-proteins. Apparently, by a complex formation with NDPK-C and caveolins (Cav), NDPK-B additionally contributes to caveolae formation and the composition of signaling complexes, e.g., G-protein-coupled receptor (GPCR) containing complexes, at the plasma membrane. Whereas the channels’ activities are linked to the indicated physiological and pathophysiological events, evidence for a contribution of the phosphorelay to the regulation of cardiac cAMP formation and thus contractility has been provided.
Mentions: One of the first phosphoproteins to be identified that contained phosphohistidine was NDPK (Walinder, 1969a; Walinder et al., 1969). Walinder et al. (1969) showed that the phosphohistidine in NDPK was an intermediate in the phosphoryl transfer reaction between NTP and NDP catalyzed by the enzyme. More recently, it was discovered that NDPK can also act as a protein histidine kinase. NDPK-A was shown to phosphorylate a histidine residue in ATP-citrate-lyase (Wagner and Vu, 1995) whilst NDPK-B phosphorylates histidine residues in the β-subunit (Gβ) of heterotrimeric G-protein βγ-dimers (Gβγ; Cuello et al., 2003), the intermediate-conductance potassium-channel SK4 (encoded by the KCNN4 gene; Srivastava et al., 2006) and the Ca2+- conducting channel, TRPV5 (Cai et al., 2014) (Figure 2). As such, NDPKs are the best characterized mammalian histidine kinases, although little is known about the details of how they recognize their substrate proteins and catalyze the phosphoryl transfer reaction. Two of the protein substrates of NDPK-B, Gβ and SK4, play important roles in cardiovascular function and disease.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Institute for Experimental and Clinical Pharmacology and Toxicology, Mannheim Medical Faculty, Heidelberg University , Mannheim, Germany.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus