PKC-interacting proteins: from function to pharmacology
ABSTRACT 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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ABSTRACT: The blood-brain barrier (BBB) is a highly specialized structural and biochemical barrier that regulates the entry of blood-borne molecules into brain, and preserves ionic homeostasis within the brain microenvironment. BBB properties are primarily determined by junctional complexes between the cerebral endothelial cells. These complexes are comprised of tight and adherens junctions. Such restrictive angioarchitecture at the BBB reduces paracellular diffusion, while minimal vesicle transport activity in brain endothelial cells limits transcellular transport. Under normal conditions, this largely prevents the extravasation of large and small solutes (unless specific transporters are present) and prevents migration of any type of blood-borne cell. However, this is changed in many pathological conditions. There, BBB disruption ("opening") can lead to increased paracellular permeability, allowing entry of leukocytes into brain tissue, but also contributing to edema formation. In parallel, there are changes in the endothelial pinocytotic vesicular system resulting in the uptake and transfer of fluid and macromolecules into brain parenchyma. This review highlights the route and possible factors involved in BBB disruption in a variety of neuropathological disorders (e.g. CNS inflammation, Alzheimer's disease, Parkinson's disease, epilepsy). It also summarizes proposed signal transduction pathways that may be involved in BBB "opening".Current Neuropharmacology 10/2008; 6(3):179-92. DOI:10.2174/157015908785777210 · 2.35 Impact Factor
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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 · 7.83 Impact Factor
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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 · 4.24 Impact Factor