Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mammalian spermatozoa should reside in the female reproductive tract for a certain time before gaining the ability to fertilize. During this time, the spermatozoa undergo a series of biochemical processes collectively called capacitation. We recently demonstrated that actin polymerization is a necessary step in the cascade leading to capacitation. We demonstrate here for the first time a role for phospholipase D (PLD) in the induction of actin polymerization and capacitation in spermatozoa. The involvement of PLD is supported by specific inhibition of F-actin formation during sperm capacitation by PLD inhibitors and the stimulation of fast F-actin formation by exogenous PLD or phosphatidic acid (PA). Moreover, PLD activity is enhanced during capacitation before actin polymerization. Protein kinase A (PKA), known to be active in sperm capacitation, and protein kinase C (PKC), involved in the acrosome reaction, can both activate PLD and actin polymerization. We suggest that PKA- and PKC-dependent signal transduction pathways can potentially lead to PLD activation; however, under physiological conditions, actin polymerization depends primarily on PKA activity. Activation of PKA during capacitation causes inactivation of phospholipase C, and as a result, PKC activation is prevented. It appears that PKA activation promotes sperm capacitation whereas early activation of PKC during capacitation would jeopardize this process.
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PMID:Crosstalk between protein kinase A and C regulates phospholipase D and F-actin formation during sperm capacitation. 1497 29

Dopamine D1-like receptors are linked via G proteins to multiple cellular signaling pathways, namely adenylyl cyclase (AC) and phospholipase C (PLC). We have previously shown that the D1-mediated inhibition of Na+-K+-ATPase activity in OK cells involves the sequential activation of the AC-protein kinase A (AC-PKA) and the PLC-protein kinase C (PLC-PKC) pathways. The present study evaluated signaling cascades involved in dopamine-mediated inhibition of Na+/H+ exchanger isoform 3 (NHE3) in rat and opossum renal cells. Na+/H+ exchanger activity was assayed as the initial rate of intracellular pH (pHi) recovery after an acid load. Vmax values (in pH units/s) for Na+-dependent pHi recovery in rat cells (0.0097+/-0.0007) were greater (P<0.05) those in opossum cells (0.0063+/-0.0007), with similar Km values (in mM) for Na+ (rat, 35+/-9; opossum, 24+/-9). The IC50 values for EIPA and amiloride induced decrease in NHE activity in rat and opossum kidney cells are in agreement with the observation that rat renal proximal tubules and opossum kidney cells express mainly the NHE3 isoform. The D1-like receptor agonist SKF 38393 inhibited NHE3 activity in a concentration-dependent manner in both rat and opossum cells. The D1-mediated inhibition of NHE3 was prevented either by the D1-like receptor antagonist SKF 83566 (1 microM), overnight treatment with cholera toxin (500 ng/ml) and the PKA antagonist H-89 (10 microM) in rat and opossum kidney cells. The effect of SKF 38393 was abolished by the PKC antagonist chelerythrine (1 microM), or the PLC inhibitor U-73,122 (3 microM) in opossum cells, but not in rat cells. In addition, dibutyril cAMP (dB-cAMP; 500 microM) was found to increase PLC activity in OK cells but not in rat cells. The effect of D1-like dopamine agonist was accompanied by increases in cyclic AMP production in rat and opossum cells. The inhibitory effect of SKF 38393 (1 microM) on NHE3 activity was abolished in rat and opossum cells pre-treated with the anti-GSalpha antibody, but not in cells treated with the anti-Gq/11 alpha antibody. It is concluded that D1 agonists decrease NHE3 activity by classical stimulation of AC and PKA via GSalpha proteins in rat kidney cells. By contrast, the D1-mediated inhibition of NHE3 in renal opossum cells involves a peculiar mechanism with AC-PKA and PLC-PKC pathways.
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PMID:Distinct signalling cascades downstream to Gsalpha coupled dopamine D1-like NHE3 inhibition in rat and opossum renal epithelial cells. 1497 10

Vasopressin neurones of the supraoptic nucleus are autoregulated by vasopressin released from their soma and dendrites. Vasopressin binds to specific autoreceptors to trigger an influx of Ca(2+), and this response involves both phospholipase C (PLC) and adenylate cyclase (AC) pathways that, in the periphery, are activated by V(1) (V(1a) and V(1b))- and V(2)-type receptors. To investigate the pathways involved in the [Ca(2+)](i) response, [Ca(2+)](i) measurements were made on freshly dissociated neurones using Fura-2 microspectrofluorimetry, and vasopressin release was measured from isolated supraoptic nuclei. The [Ca(2+)](i) increase and vasopressin release induced by the V(1a) agonist were strongly inhibited by a PLC blocker, an IP(3) receptor antagonist, and a PKC blocker. An AC inhibitor did not affect the V(1a) response, while PKA inhibitors significantly reduced the V(1a)-induced [Ca(2+)](i) and release responses. The [Ca(2+)](i) increase and vasopressin release elicited by the V(2) agonist were attenuated not only by AC pathway blockers, but also by PLC inhibitors. Surprisingly, the V(1b) agonist showed no [Ca(2+)](i) or vasopressin release response. In conclusion, the V(1a) agonist activates both PLC and AC pathway, confirming the functional expression of a V(1a) vasopressin receptor on vasopressin neurones. The V(2) agonist activation of both PLC and AC pathways could result from an action on the PLC-linked unknown receptor, and/or the AC-linked dual angiotensin II-vasopressin receptor.
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PMID:Intracellular calcium increase and somatodendritic vasopressin release by vasopressin receptor agonists in the rat supraoptic nucleus: involvement of multiple intracellular transduction signals. 1504 53

The recent achievements on phosphoinositide signaling in the unicellular eukaryotes have been reviewed. Special attention is paid to mechanisms of phospholipase C (PLC) activation and its interaction with both cell surface receptors and effector cytoplasm targets. We discuss the role of protein kinase C (PKC) in intracellular signaling, and the relationship between the PI-signal pathway key enzymes with protein kinases of cAMP-PKA and MAP-kinase pathways.
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PMID:[The role of phosphoinositide signaling in the lower eukaryotes]. 1517 52

This study evaluated the transduction pathway associated with type 3 Na(+)/H(+) exchanger (NHE3) activity-induced inhibition during dopamine D(3) receptor activation in immortalized renal proximal tubular epithelial cells from the spontaneously hypertensive rat. The dopamine D(3) receptor agonist 7-OH-DPAT decreased NHE3 activity, which was prevented by the D(2)-like receptor antagonist S-sulpiride, pertussis toxin (PTX; overnight treatment), and the PKC inhibitor chelerythrine, but not by cholera toxin (overnight treatment), the MAPK inhibitor PD-098059, or the p38 inhibitor SB-203580. The PKA inhibitor H-89 abolished the inhibitory effects of forskolin on NHE3 activity, but not that of 7-OH-DPAT. The phospholipase C (PLC) inhibitor U-73122 prevented the inhibitory effects of 7-OH-DPAT, whereas PDBu and 7-OH-DPAT increased PLC activity and reduced NHE3 activity; downregulation of PKC abolished the inhibitory effects of both PDBu and 7-OH-DPAT on NHE activity. The inhibition of NHE3 activity by GTPgammaS and the prevention of the effect of 7-OH-DPAT by PTX suggest an involvement of a G(i/o) protein coupled to the dopamine D(3) receptor. Indeed, the 7-OH-DPAT-induced decrease in NHE3 activity was abolished in cells treated overnight with the anti-G(i)alpha3 antibody, but not in cells treated with antibodies against G(q/11), G(s)alpha, G(beta), and G(i)alpha1,2 proteins. The calcium ionophore A-23187 and the Ca(2+)-ATPase inhibitor thapsigargin increased intracellular Ca(2+) but did not affect NHE3 activity. However, the inhibitory effects of PDBu and 7-OH-DPAT on NHE3 activity were completely abolished by A-23287 and thapsigargin. It is concluded that inhibition of NHE3 activity by dopamine D(3) receptors coupled to G(i)alpha3 proteins is a PLC-PKC-mediated event, modulated by intracellular Ca(2+).
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PMID:Gialpha3 protein-coupled dopamine D3 receptor-mediated inhibition of renal NHE3 activity in SHR proximal tubular cells is a PLC-PKC-mediated event. 1526 66

Cordyceps sinensis (CS) mycelium stimulates steroidogenesis in MA-10 mouse Leydig tumor cells, but the mechanisms remain unclear. In this study, MA-10 cells were treated with different reagents in the presence or absence of CS (10 mg/ml) for 3 h to determine the mechanisms. Results illustrated that CS activated the Gsalpha protein subunit, but not Gialpha, to induce cell steroidogenesis. Moreover, PKA inhibitors inhibited 37% of CS-stimulated steroidogenesis, which demonstrated that CS might enhance the cAMP-PKA pathway to affect MA-10 cell steroidogenesis. Because of incomplete inhibition by PKA inhibitors, we also examined the PKC pathway. PKC inhibitor, phospholipase C inhibitor, and calmodulin antagonist blocked 35-52% of CS-stimulated steroidogenesis in MA-10 cells, strongly suggesting that CS had activated the PKC pathway. Co-treatment with PKA and PKC inhibitors abolished 61% of CS-stimulated steroid production, indicating that CS simultaneously activated PKA and PKC pathways. Moreover, CS induced the expression of steroidogenic acute regulatory (StAR) protein in dose- and time-dependent relationships, and PKA inhibitor, PKC inhibitor, or co-treatment with both inhibitors suppressed it. These data support that CS activates both PKA and PKC signal transduction pathways to stimulate MA-10 cell steroidogenesis.
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PMID:Cordyceps sinensis mycelium activates PKA and PKC signal pathways to stimulate steroidogenesis in MA-10 mouse Leydig tumor cells. 1538 Nov 63

Opioids were found as factors affecting porcine ovarian steroidogenesis. The mechanism of opioid action, however, on porcine theca interna cells is completely unknown. Therefore, the present study was designed to investigate the possible involvement of two intracellular pathways, phospholipase C/protein kinase C and adenylyl cyclase/protein kinase A, in opioid signal transduction in porcine theca cells treated with mu opioid receptor agonist, FK 33-824. Incubation of the cells for 4 h with FK 33-824 at the dose 1 nM resulted in decreases in inositol phosphate accumulation as well as androstenedione (A(4)), testosterone (T), and estradiol (E(2)) secretions. Protein kinase C (PKC) inhibitors, staurosporine (1-100 nM), D-sphingosine (10-500 nM), and PKCi (100-2000 nM), both added alone and together with the opioid agonist, depressed release of the steroid hormones. PKC activator, phorbol ester (PMA, 1-100 nM), used alone was without effect on theca cell steroidogenesis, but added in combination with FK 33-824 abolished inhibitory influence of the opioid on A(4), T, and E(2) output. The steroid hormone secretion by PKC-deficient theca cells was inhibited by the opioid agonist. FK 33-824 also suppressed PKC activity reducing [(3)H]PDBu specific binding to theca cells, whereas ionomycin (a positive control) increased labeled phorbol ester binding to the cells. In the next experiment, cAMP release from theca cells during 2 and 4 h incubations with FK 33-824 (1-100 nM), naloxone (10 microM; opioid receptor antagonist), and LH (100 ng/mL; a positive control) was examined. FK 33-824 at the dose 1 nM inhibited cAMP secretion during 2 h incubation, but had no effect during longer incubation. LH in a manner independent on incubation time multiplied cAMP release. Protein kinase A inhibitor, PKAi (100-2000 nM), alone and in combination with FK 33-824 (1 nM), inhibited A(4), T, and E(2) secretions by theca cells. PKA activator, 8BrcAMP (10-1000 microM), stimulated the steroid hormone release, but this stimulatory effect was diminished in the presence of FK 33-824. The results allow to suggest that opioid peptides affect porcine theca cell steroidogenesis and their acute action on the cells is connected with the inhibition of phospholipase C/protein kinase C and adenylyl cyclase/protein kinase A signal transduction systems.
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PMID:The response of phospholipase C/protein kinase C and adenylyl cyclase/protein kinase A pathways in porcine theca interna cells to opioid agonist FK 33-824. 1551 41

Recently, we demonstrated that the mammalian type-I GnRH receptor (GnRHR) has a high preference for the phospholipase C/protein kinase C (PLC/PKC)-linked signaling pathway, whereas non-mammalian bullfrog (bf) GnRHRs couple to both adenylate cyclase/protein kinase A (AC/PKA)- and PLC/PKC-linked signaling pathways. In the pre-sent study, using AC/PKA-specific reporter (cAMP-responsive element-luciferase) and PLC/PKC-specific reporter (serum-responsive element-luciferase) systems, we attempted to identify the motif responsible for this difference. A deletion of the intracellular carboxyl-terminal tail (C tail) of bfGnRHR-1 remarkably decreased its ability to induce the AC/PKA-linked signaling pathway. Further dissection of the C tail indicated that an HFRK motif in the membrane-proximal sequence of bfGnRHR-1 C tail is a minimal requirement for the AC/PKA-linked signaling pathway as the addition of this motif to rat GnRHR or deletion of it from bfGnRHR-1 significantly affected the ability to induce the AC/PKA-linked signaling pathway. Deletion or addition of the HFRK motif, however, did not critically influence the PLC/PKC-linked signaling pathway. These results indicate that the HFRK motif in the membrane-proximal region confers the differential signal transduction pathways between mammalian and nonmammalian GnRHRs.
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PMID:Membrane-proximal region of the carboxyl terminus of the gonadotropin-releasing hormone receptor (GnRHR) confers differential signal transduction between mammalian and nonmammalian GnRHRs. 1556 46

Receptor-mediated dopamine (DA) modulation of neuronal excitability in the nucleus accumbens (NAc) has been shown to be critically involved in drug addiction and a variety of brain diseases. However, the mechanisms underlying the physiological or pathological molecular process of DA modulation remain largely elusive. Here, we demonstrate that stimulation of DA D2 class receptors (D2R) enhanced voltage-sensitive sodium currents (VSSCs, I(Na)) in freshly dissociated NAc neurons via suppressing tonic activity of the cyclic AMP/PKA cascade and facilitating intracellular Ca2+ signaling. D2R-mediated I(Na) enhancement depended on activation of G(i/o) proteins and was mimicked by direct inhibition of PKA. Furthermore, increasing free [Ca2+]in by activating inositol 1,4,5-triphosphate receptors (IP3Rs), blocking Ca2+ reuptake, or adding buffered Ca2+, all enhanced I(Na). Under these circumstances, D2R-mediated I(Na) enhancement was occluded. In contrast, D2R-mediated I(Na) enhancement was blocked by inhibition of IP3Rs, chelation of free Ca2+, or inhibition of Ca2(+)/calmodulin-activated calcineurin (CaN), but not by inhibition of phospholipase C (PLC). Although stimulation of muscarinic cholinergic receptors (mAChRs) also increased I(Na), this action was blocked by PLC inhibitors. Our findings indicate that D2Rs mediate an enhancement of VSSCs in NAc neurons, in which cytosolic free Ca2+ plays a crucial role. Our results also suggest that D2R-mediated reduction in tonic PKA activity may increase free [Ca2+]in, primarily via disinhibition of IP3Rs. IP3R activation then facilitates Ca2+ signaling and subsequently enhances VSSCs via decreasing PKA-induced phosphorylation and increasing CaN-induced dephosphorylation of Na+ channels. This study provides insight into the complex and dynamic role of D2Rs in the NAc.
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PMID:Dopamine D2 receptor-activated Ca2+ signaling modulates voltage-sensitive sodium currents in rat nucleus accumbens neurons. 1559 Jul 33

Cell membranes isolated from brain tissues, obtained surgically from six patients afflicted with drug-resistant temporal lobe epilepsy and from one nonepileptic patient afflicted with a cerebral oligodendroglioma, were injected into frog oocytes. By using this approach, the oocytes acquire human GABAA receptors, and we have shown previously that the "epileptic receptors" (receptors transplanted from epileptic brains) display a marked run-down during repetitive applications of GABA. It was found that exposure to the neurotrophin BDNF increased the amplitude of the "GABA currents" (currents elicited by GABA) generated by the epileptic receptors and decreased their run-down; both events being blocked by K252A, a neurotrophin tyrosine kinase receptor B inhibitor. These effects of BDNF were not mimicked by nerve growth factor. In contrast, the GABAA receptors transplanted from the nonepileptic human hippocampal uncus (obtained during surgical resection as part of the nontumoral tissue from the oligodendroglioma margins) or receptors expressed by injecting rat recombinant alpha1beta2gamma2 GABAA receptor subunit cDNAs generated GABA currents whose time-course and run-down were not altered by BDNF. Loading the oocytes with the Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetate-acetoxymethyl ester (BAPTA-AM), or treating them with Rp-8-Br-cAMP, an inhibitor of the cAMP-dependent PKA, did not alter the GABA currents. However, staurosporine (a broad spectrum PK inhibitor), bisindolylmaleimide I (a PKC inhibitor), and U73122 (a phospholipase C inhibitor) blocked the BDNF-induced effects on the epileptic GABA currents. Our results indicate that BDNF potentiates the epileptic GABAA currents and antagonizes their use-dependent run-down, thus strengthening GABAergic inhibition, probably by means of activation of tyrosine kinase receptor B receptors and of both PLC and PKC.
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PMID:BDNF modulates GABAA receptors microtransplanted from the human epileptic brain to Xenopus oocytes. 1566 77


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