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Reciprocal modulation of phospholipase Cbeta isoforms: adaptation to chronic morphine.

ABSTRACT: Phosphoinositide turnover and calcium mobilization are fundamental determinants of acute and chronic opioid effects. Phosphoinositide-specific phospholipase C (PLC) are key signaling enzymes that play a pivotal role in mediating opioid modulation of inositol trisphosphate production and cytosolic calcium distribution, substrates for many acute and chronic opioid effects. Notably, phosphorylation of the beta isoforms of PLC, by kinases that are up-regulated after chronic morphine, is a potent modality for their regulation. Direct assessment of PLCbeta1 and PLCbeta3 phosphorylation in the guinea pig longitudinal muscle myenteric plexus tissue revealed substantial alterations after the induction of opioid tolerance. Notably, the direction of this modulation is isoform-specific. Phosphorylation of PLCbeta1 is significantly reduced, whereas that of PLCbeta3 is substantially augmented, changes not accompanied by altered content of PLCbeta1 or PLCbeta3 protein. In contrast to chronic morphine, acute morphine treatment of opioid naïve longitudinal muscle myenteric plexus tissue attenuates PLCbeta3 phosphorylation, an effect also manifested by endogenous opioids that is reflected by the ability of acute naloxone to substantially augment PLCbeta3 phosphorylation. This indicates that PLCbeta phosphorylation is dynamically regulated. PLCbeta1 and PLCbeta3 activities are negatively modulated by phosphorylation. Thus, their concomitant reciprocal phosphorylation would alter the relative contribution of these isoforms to PLC/Ca2+ signaling, a significant shift in light of their differential regulatory characteristics. Reciprocal modulation of the phosphorylation (activity) of two isoforms within the same subclass of signaling enzyme, proteins that have a high degree of structural similarity and subserve the same biological function, represents an adaptation modality to chronic morphine that has heretofore not been recognized.

SUBMITTER: Chakrabarti S

PROVIDER: S-EPMC263874 | biostudies-other | 2003 Nov

REPOSITORIES: biostudies-other

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Project description:Phospholipase C (PLC) comprises a superfamily of enzymes that play a key role in a wide array of intracellular signalling pathways, including protein kinase C and intracellular calcium. Thirteen different mammalian PLC isoforms have been identified and classified into 6 families (PLC-β, γ, δ, ε, ζ and η) based on their biochemical properties. Although the expression of PLC isoforms is tissue-specific, concomitant expression of different PLC has been reported, suggesting that PLC family is involved in multiple cellular functions. Despite their critical role, the PLC isoforms expressed in native endothelial cells (ECs) remains undetermined. A conventional PCR approach was initially used to elucidate the mRNA expression pattern of PLC isoforms in 3 distinct murine vascular beds: mesenteric (MA), pulmonary (PA) and middle cerebral arteries (MCA). mRNA encoding for most PLC isoforms was detected in MA, MCA and PA with the exception of η2 and β2 (only expressed in PA), δ4 (only expressed in MCA), η1 (expressed in all but MA) and ζ (not detected in any vascular beds tested). The endothelial-specific PLC expression was then sought in freshly isolated ECs. Interestingly, the PLC expression profile appears to differ across the investigated arterial beds. While mRNA for 8 of the 13 PLC isoforms was detected in ECs from MA, two additional PLC isoforms were detected in ECs from PA and MCA. Co-expression of multiple PLC isoforms in ECs suggests an elaborate network of signalling pathways: PLC isoforms may contribute to the complexity or diversity of signalling by their selective localization in cellular microdomains. However in situ immunofluorescence revealed a homogeneous distribution for all PLC isoforms probed (β3, γ2 and δ1) in intact endothelium. Although PLC isoforms play a crucial role in endothelial signal transduction, subcellular localization alone does not appear to be sufficient to determine the role of PLC in the signalling microdomains found in the native endothelium.

Project description:Neuron differentiation is a complex process involving various cell-cell interactions, and multiple signaling pathways. We showed previously that CD40 is expressed and functional on mouse and human neurons. In neurons, ligation of CD40 protects against serum withdrawal-induced injury and plays a role in survival and differentiation. CD40 deficient mice display neuron dysfunction, aberrant neuron morphologic changes, and associated gross brain abnormalities. Previous studies by Tone and colleagues suggested that five isoforms of CD40 exist with two predominant isoforms expressed in humans: signal-transducible CD40 type I and a C-terminal truncated, non-signal-transducible CD40 type II. We hypothesized that differential expression of CD40 isoform type I and type II in neurons may modulate neuron differentiation. Results show that adult wild-type, and CD40(-/-) deficient mice predominantly express CD40 type I and II isoforms. Whereas adult wild-type mice express mostly CD40 type I in cerebral tissues at relatively high levels, in age and gender-matched CD40(-/-) mice CD40 type I expression was almost completely absent; suggesting a predominance of the non-signal-transducible CD40 type II isoform. Younger, 1 day old wild-type mice displayed less CD40 type I, and more CD40 type II, as well as, greater expression of soluble CD40 (CD40L/CD40 signal inhibitor), compared with 1 month old mice. Neuron-like N2a cells express CD40 type I and type II isoforms while in an undifferentiated state, however once induced to differentiate, CD40 type I predominates. Further, differentiated N2a cells treated with CD40 ligand express high levels of neuron specific nuclear protein (NeuN); an effect reduced by anti-CD40 type I siRNA, but not by control (non-targeting) siRNA. Altogether these data suggest that CD40 isoforms may act in a temporal fashion to modulate neuron differentiation during brain development. Thus, modulation of neuronal CD40 isoforms and CD40 signaling may represent important therapeutic modalities for neurodegenerative and neurodevelopmental disorders, as well as, for enhancement of neurogenesis.

Project description:BackgroundHigh level piano performance requires complex integration of perceptual, motor, cognitive and emotive skills. Observations in psychology and neuroscience studies have suggested reciprocal inhibitory modulation of the cognition by emotion and emotion by cognition. However, it is still unclear how cognitive states may influence the pianistic performance. The aim of the present study is to verify the influence of cognitive and affective attention in the piano performances.Methods and findingsNine pianists were instructed to play the same piece of music, firstly focusing only on cognitive aspects of musical structure (cognitive performances), and secondly, paying attention solely on affective aspects (affective performances). Audio files from pianistic performances were examined using a computational model that retrieves nine specific musical features (descriptors)--loudness, articulation, brightness, harmonic complexity, event detection, key clarity, mode detection, pulse clarity and repetition. In addition, the number of volunteers' errors in the recording sessions was counted. Comments from pianists about their thoughts during performances were also evaluated. The analyses of audio files throughout musical descriptors indicated that the affective performances have more: agogics, legatos, pianos phrasing, and less perception of event density when compared to the cognitive ones. Error analysis demonstrated that volunteers misplayed more left hand notes in the cognitive performances than in the affective ones. Volunteers also played more wrong notes in affective than in cognitive performances. These results correspond to the volunteers' comments that in the affective performances, the cognitive aspects of piano execution are inhibited, whereas in the cognitive performances, the expressiveness is inhibited.ConclusionsTherefore, the present results indicate that attention to the emotional aspects of performance enhances expressiveness, but constrains cognitive and motor skills in the piano execution. In contrast, attention to the cognitive aspects may constrain the expressivity and automatism of piano performances.

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Reciprocal modulation of phospholipase Cbeta isoforms: adaptation to chronic morphine.

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