The role of protein kinase C-mediated phosphorylation of sarcomeric proteins in the heart—detrimental or beneficial?

Abstract

Protein kinase C (PKC) is a family of serine/ threonine protein kinases, and alterations have been found in PKC isoform expression and localization in the failing heart. These alterations in PKC activation levels influence the PKC-mediated phosphorylation status of cellular target proteins involved in Ca 2+ -handling and sarcomeric contraction. The differences observed in the effects due to PKCmediated phosphorylation may underlie part of the contractile dysfunction observed in the failing heart. It is therefore important to establish the beneficial and detrimental effects of this kinase in the healthy and failing heart. The function of PKC has been studied intensively; however, the complexity of the regulation of this kinase makes the interpretation of the different effects difficult. The main focus of this review is the (patho)physiological impact of phosphorylation of sarcomeric proteins, myosin light chain-2, troponin I and T, desmin, myosin binding protein-C, and titin by PKC.

PKC and PKN in heart disease

“…References PKCs myofibrillar myosin light chain-2 (MLC2v; rat Ser15) modulation of force generation [166] titin (PEVK region; Ser11878, Ser12022) modulation of titin compliance [167] muscle lim protein (MLP, CSRP3) modulation of PKC activity [42] muscle ankyrin repeat proteins (Ankrd1/CARP1, Thr11, Thr116, Ser305; Ankrd2/CARP2; Ankrd23/ CARP3) unknown, potential regulation of stretch-responsive signaling pathways [168] troponin-I (Ser42, Ser44, Ser76, Ser198, Thr143, Ser198) modulation of force generation [169][170][171][172][173][174][175] troponin-T (Ser1, Thr194, Ser198, Thr203 and Thr284, Ser179) myosin binding protein-C (MyBPC, Ser275, Ser302, Ser304) modulation of force generation [69,166] ion channels & pumps, membrane-associated proteins L-type calcium channel Ca(v)1.2 (α1C-subunit, Ser1674, Ser1928) increased channel activity [59,176] Connexin-43 (Cx43, Ser368) regulation of subcellular Cx43 distribution [177] K(v)1.5 channel (Kvβ1.3 regulatory subunit) modulation of channel activity [70] ryanodine receptor (RyR) modulation of channel activity [178] sarcoendoplasmic reticulum Ca 2+ -ATPase (SERCA) modulation of SERCA activity [179] phospholamban (PLN, Ser16, Ser10?) modulation of SERCA activity, unknown roles for Ser10 phosphorylation [60,61] vinculin (Ser1033, Ser1045) modulation of lipid-docking [180] signaling β2-adrenergic receptor (β2-AR; Ser261, Ser262, Ser344, Ser345) modulation of adrenergic signaling & force generation [181] G-protein coupled receptor kinase (GRK2, Ser29; GRK5) enhances GRK activity, modulation of adrenergic signaling [182,183] histone deacetylase 5 (HDAC5; Ser259, Ser498) modulation of nuclear shuttling and transcriptional activity [34,184] signal transducer and activator of transcription 3 (STAT3, Ser727?)…”

Involvement of O-GlcNAcylation in the Skeletal Muscle Physiology and Physiopathology: Focus on Muscle Metabolism

“…Within the unitary contractile apparatus, named sarcomere, and more generally in the overall skeletal muscle cell, diverse proteins have been identified to be O-GlcNAcylated since 2004 ( 18 , 40 – 43 ); the nature of these proteins is diversified including contractile, structural, cytoskeletal, metabolic, chaperones, mitochondrial proteins or proteins involved in signaling pathways. Thus, akin to phosphorylation ( 37 , 44 , 45 ), O-GlcNAcylation could play a significant role, still undervalued, in the skeletal muscle physiology.…”

Gene regulation, alternative splicing, and posttranslational modification of troponin subunits in cardiac development and adaptation: a focused review

“…While PKA phosphorylation of cardiac TnI at Ser 23 /Ser 24 increases myocardial relaxation, PKC phosphorylation of cardiac TnI exerts an antithetic role (Sakthivel et al, 2005 ; Kooij et al, 2011 ). PKC phosphorylates cardiac TnI at Ser 43 and Ser 45 (residue # in mouse sequence) in the region binding the C domain of TnC and Thr 144 in the inhibitory region, slowing cardiac relaxation and increasing the duration of calcium transient and twitch contraction (Macgowan et al, 2001 ; Pi et al, 2002 ; Burkart et al, 2003b ; Westfall et al, 2005 ).…”