PKC-interacting proteins: from function to pharmacology. Trends Pharmacol Sci

Department of Pharmacology, School of Medical Sciences, University Walk, Bristol BS8 1TD, UK.
Trends in Pharmacological Sciences (Impact Factor: 11.54). 11/2004; 25(10):528-35. DOI: 10.1016/
Source: PubMed


Protein kinase C (PKC) is a ubiquitously expressed family of kinases that have key roles in regulating multiple cellular activities. The activity of this family is controlled tightly by several molecular mechanisms, including interaction with binding-partner proteins. These PKC-interacting proteins (C-KIPs) confer specificity for individual PKC isoforms by regulating the activity and cellular localization of PKC isoforms and, subsequently, the ability of these isoforms to specifically regulate cellular functional events. Although many C-KIPs have been identified by genome and proteome-mining approaches, it is important to address the specificity and function of the interactions in greater detail because they might form novel drug targets. In this article, we review recent work on C-KIPs and the implications for pharmacological and therapeutic development.

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    • "Another intriguing possibility is that EtOH may target PKC isozyme-specific interacting proteins present in the membrane fraction. Indeed, a number of PKC isozymespecific interacting proteins have been identified, which might regulate PKC activity (Poole et al, 2004). In this regard, EtOH has been shown to promote the uncoupling of the scaffolding protein, RACK1, from PKCb 2 (Ron et al, 2000). "
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    ABSTRACT: Ethanol consumption potentiates dopaminergic signaling that is partially mediated by the D(1) dopamine receptor; however, the mechanism(s) underlying ethanol-dependent modulation of D(1) signaling is unclear. We now show that ethanol treatment of D(1) receptor-expressing cells decreases D(1) receptor phosphorylation and concurrently potentiates dopamine-stimulated cAMP accumulation. Protein kinase C (PKC) inhibitors mimic the effects of ethanol on D(1) receptor phosphorylation and dopamine-stimulated cAMP levels in a manner that is non-additive with ethanol treatment. Ethanol was also found to modulate specific PKC activities as demonstrated using in vitro kinase assays where ethanol treatment attenuated the activities of lipid-stimulated PKCgamma and PKCdelta in membrane fractions, but did not affect the activities of PKCalpha, PKCbeta(1), or PKCvarepsilon. Importantly, ethanol treatment potentiated D(1) receptor-mediated DARPP-32 phosphorylation in rat striatal slices, supporting the notion that ethanol enhances D(1) receptor signaling in vivo. These findings suggest that ethanol inhibits the activities of specific PKC isozymes, resulting in decreased D(1) receptor phosphorylation and enhanced dopaminergic signaling.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 03/2008; 33(12):2900-11. DOI:10.1038/npp.2008.16 · 7.05 Impact Factor
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    • "o trigger novel PKCs , their C2 domain contains other targeting sequences involved in activation or subcellular translocation ( Table 1 ) ( Giorgione et al . 2006 ; Zhu et al . 2006 ) . While tyrosine phosphorylation is an important driving factor in PKCd ( Steinberg 2004 ) , RACK binding contributes to uncover the kinase domain PKCe ( Fig . 2 ) ( Poole et al . 2004 ; Schechtman et al . 2004 ; Brandman et al . 2007 ) . This RACK has been identified as b¢ - coatomer protein , a coatomer protein I complex protein associated to Golgi"
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    ABSTRACT: Despite the apparent homology in the protein kinase C (PKC) family, it has become clear that slight structural differences are sufficient to have unique signalling properties for each individual isoform. For PKCepsilon in depth investigation of these aspects revealed unique actions in the CNS and lead to development of specific modulators with clinical perspective. In this review, we describe to which extent PKCepsilon is distinct from other isoforms on the level of tissue expression and protein structure. As this kinase is highly expressed in the brain, we outline three main aspects of PKCepsilon signalling in the CNS. First, its ability to alter the permeability of N-type Ca2+ channels in dorsal root ganglia has been shown to enhance nociception. Secondly, PKCepsilon increases anxiety by diminishing GABA(A)R-induced inhibitory post-synaptic currents in the prefrontal cortex. Another important aspect of the latter inhibition is the reduced sensitivity of GABA(A) receptors to ethanol, a mechanism potentially contributing to abuse. A third signalling cascade improves cognitive functions by facilitating cholinergic signalling in the hippocampus. Collectively, these findings point to a physical and behavioural sensitising role for this kinase.
    Journal of Neurochemistry 02/2008; 104(1):1-13. DOI:10.1111/j.1471-4159.2007.04986.x · 4.28 Impact Factor
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    • "Within the cell however, PKC isozymes mediate unique cellular functions by phosphorylating specific subsets of target proteins. Such substrate specificity is most likely conferred by differential targeting of activated PKC isoforms to distinct subcellular locations governed by the distribution of their preferred substrate [22] [23] [24]. We have shown recently that vascular K ATP channels localize primarily to small vesicular invaginations of the plasma membrane termed caveolae [25]. "
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    ABSTRACT: The vasoconstrictor angiotensin II (Ang II) acts at G(q/11)-coupled receptors to suppress ATP-sensitive potassium (K(ATP)) channel activity via activation of protein kinase C (PKC). The aim of this study was to determine the PKC isoforms involved in the Ang II-induced inhibition of aortic K(ATP) channel activity and to investigate potential mechanisms by which these isoforms specifically target these ion channels. We show that the inhibitory effect of Ang II on pinacidil-evoked whole-cell rat aortic K(ATP) currents persists in the presence of Gö6976, an inhibitor of the conventional PKC isoforms, but is abolished by intracellular dialysis of a selective PKCepsilon translocation inhibitor peptide. This suggests that PKC-dependent inhibition of aortic K(ATP) channels by Ang II arises exclusively from the activation and translocation of PKCepsilon. Using discontinuous sucrose density gradients and Western blot analysis, we show that Ang II induces the translocation of PKCepsilon to cholesterol-enriched rat aortic smooth muscle membrane fractions containing both caveolin, a protein found exclusively in caveolae, and Kir6.1, the pore-forming subunit of the vascular K(ATP) channel. Immunogold electron microscopy of rat aortic smooth muscle plasma membrane sheets confirms both the presence of Kir6.1 in morphologically identifiable regions of the membrane rich in caveolin and Ang II-evoked migration of PKCepsilon to these membrane compartments. Ang II induces the recruitment of the novel PKC isoform, PKCepsilon, to arterial smooth muscle caveolae. This translocation allows PKCepsilon access to K(ATP) channels compartmentalized within these specialized membrane microdomains and highlights a potential role for caveolae in targeting PKC isozymes to an ion channel effector.
    Cardiovascular Research 11/2007; 76(1):61-70. DOI:10.1016/j.cardiores.2007.05.020 · 5.94 Impact Factor
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