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

Hypothalamic proopiomelanocortin (POMC) neurons play a critical role in the regulation of energy balance, and there is a convergence of critical synaptic input including GABA and serotonin on POMC neurons to regulate their output. We found previously that 17beta-estradiol (E(2)) reduced the potency of the GABA(B) receptor agonist baclofen to activate G protein-coupled inwardly rectifying potassium (GIRK) channels in hypothalamic POMC neurons through a membrane estrogen receptor (mER) via a Galpha(q) phospholipase C (PLC)-protein kinase Cdelta-protein kinase A pathway. We hypothesized that the mER and neurotransmitter receptor signaling pathways converge to control energy homeostasis. Because 5-HT(2C) receptors mediate many of the effects of serotonin in POMC neurons, we elucidated the common signaling pathways of E(2) and 5-HT in guinea pigs using single-cell reverse transcription-polymerase chain reaction (RT-PCR), real time RT-PCR, and whole-cell patch recording. Both 5-hydroxytryptamine(2C) (5-HT(2C)) and 5-HT(2A) receptors were coexpressed in POMC neurons. The 5-HT(2A/C) agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) desensitized the GABA(B) response in a dose-dependent manner, which was antagonized by the selective 5-HT(2C) receptor antagonists 8-[5-(2,4-dimethoxy-5-(4-trifluoromethylphenylsulphonamido) phenyl-5-oxopentyl]1,3,8-triazaspiro[4.5] decane-2,4-dione hydrochloride (RS102221) and 1,2,3, 4,10,14b-hexahydro-2-methyldibenzo [c,f]pyrazino[1,2-a]-azepine hydrochloride (ORG 3363). The 5-HT(2C) receptor was Galpha(q)-coupled to PLC activation and hydrolysis of plasma membrane phosphatidylinositol bisphosphate to directly inhibit GIRK channel activity. Coapplication of the two agonists at their EC(50) concentrations (DOI, 20 muM, and E(2), 50 nM) produced additive effects. Although there was a significant gender difference in the effects of E(2) on baclofen responses, there was no gender difference in 5-HT(2C) receptor-mediated effects. Finally, both DOI and estrogen (intracerebroventricular) inhibited feeding in ovariectomized female mice. Therefore, the Galpha(q) signaling pathways of the mER and 5-HT(2C) receptors may converge to enhance synaptic efficacy in brain circuits that are critical for maintaining homeostatic functions.
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PMID:Serotonin 5-hydroxytryptamine2C receptor signaling in hypothalamic proopiomelanocortin neurons: role in energy homeostasis in females. 1762 77

Progestin-facilitated lordosis of rodents is enhanced by activation of dopamine type 1 (D(1)) or GABA(A) receptors, their downstream G-proteins, and/or second messengers in the ventral tegmental area (VTA). We examined whether the ability of progestins to enhance lordosis via actions at D(1) and/or GABA(A) receptors is contingent upon activation of the second messenger phospholipase C (PLC) and its associated kinase, protein kinase C (PKC), in the VTA. If the actions of progestins through D(1) and GABA(A) receptors in the VTA are mediated through PLC and PKC, then inhibiting PLC formation (Experiment 1) or blocking PKC (Experiment 2) should reduce progestin-facilitated lordosis and its enhancement by D(1) (SKF38393) or GABA(A) (muscimol) receptor agonists. In Experiment 1, ovariectomised hamsters, primed with oestradiol (10 microg; h 0) + progesterone (100 microg; h 45), were pretested for lordosis and motor behaviour (h 48) and then infused with the PLC inhibitor, U73122 (400 nM/side), or vehicle. Thirty minutes later, hamsters were retested and then received infusions of SKF38393 (100 ng/side), muscimol (100 ng/side), or vehicle to the VTA. Hamsters were post-tested for lordosis and motor behaviour 30 min later. In Experiment 2, a similar protocol was utilised except that instead of the PLC inhibitor hamsters were infused with the PKC inhibitor, bisindolylmaleimide (75 nM/side). Systemic progesterone, SKF38393-, and muscimol-facilitated lordosis was attenuated by infusion of the PLC inhibitor, U73122, or the PKC inhibitor, bisindolylmaleimide, compared to vehicle to the VTA. Thus, the actions of progestins in the VTA to enhance lordosis through D(1) and/or GABA(A) may include downstream activity of PLC and PKC.
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PMID:In the ventral tegmental area, the membrane-mediated actions of progestins for lordosis of hormone-primed hamsters involve phospholipase C and protein kinase C. 1768 Aug 87

GABA(A) receptors are heteropentameric ligand-gated chloride channels composed of a variety of subunits, including alpha1 - 6, beta1 - 3, gamma1 - 3, delta, epsilon, theta, and pi, and play a key role in controlling inhibitory neuronal activity. Modification of the efficacy of the synaptic strength is produced by changes in both the number of neuronal surface receptors and pentameric molecular assembly, leading to differences of sensitivity to neurotransmitters and neuromimetic drugs. Therefore, it is important to understand the molecular mechanisms regulating the so-called "life cycle of GABA(A) receptors" including sequential pentameric assembly at the site synthesized, intracellular transport through the Golgi apparatus and the cytoplasm, insertion into the cell membrane, functional modulation at the cell surface, and finally internalization, followed by either recycling back to the surface membrane or lysosomal degradation. This review is focused on events related to the surface expression of the receptor containing the gamma2 subunit and clathrin/AP2 complex-mediated phospho-regulated endocytosis of the receptor, with special reference to the function of novel GABA(A) receptor modulators, GABARAP (GABA(A) receptor-associated protein) and PRIP (phospholipase C-related, but catalytically inactive protein).
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PMID:Regulation of GABA(A)-receptor surface expression with special reference to the involvement of GABARAP (GABA(A) receptor-associated protein) and PRIP (phospholipase C-related, but catalytically inactive protein). 1769 May 29

Whereas the entorhinal cortex (EC) receives noradrenergic innervations from the locus coeruleus of the pons and expresses adrenergic receptors, the function of norepinephrine (NE) in the EC is still elusive. We examined the effects of NE on GABA(A) receptor-mediated synaptic transmission in the superficial layers of the EC. Application of NE dose-dependently increased the frequency and amplitude of spontaneous inhibitory postsynaptic currents (IPSCs) recorded from the principal neurons in layer II/III through activation of alpha(1) adrenergic receptors. NE increased the frequency and not the amplitude of miniature IPSCs (mIPSCs) recorded in the presence of TTX, suggesting that NE increases presynaptic GABA release with no effects on postsynaptic GABA(A) receptors. Application of Ca(2+) channel blockers (Cd(2+) and Ni(2+)), omission of Ca(2+) in the extracellular solution, or replacement of extracellular Na(+) with N-methyl-D-glucamine (NMDG) failed to alter NE-induced increase in mIPSC frequency, suggesting that Ca(2+) influx through voltage-gated Ca(2+) or other cationic channels is not required. Application of BAPTA-AM, thapsigargin, and ryanodine did not change NE-induced increase in mIPSC frequency, suggesting that Ca(2+) release from intracellular stores is not necessary for NE-induced increase in GABA release. Whereas alpha(1) receptors are coupled to G(q/11) resulting in activation of the phospholipase C (PLC) pathway, NE-mediated facilitation of GABAergic transmission was independent of PLC, protein kinase C, and tyrosine kinase activities. Our results suggest that NE-mediated facilitation of GABAergic function contributes to its antiepileptic effects in the EC.
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PMID:Adrenergic facilitation of GABAergic transmission in rat entorhinal cortex. 1780 73

Long-term potentiation (LTP) of excitatory synapses on GABAergic neurons in layer II/III of visual cortical slices was examined in GAD67-GFP knock-in mice by whole-cell recordings of EPSPs evoked by layer IV stimulation. Theta burst stimulation (TBS) paired with postsynaptic depolarization induced LTP in 14 of 19 fast-spiking GABAergic (FS-GABA) neurons, whereas only in 6 of 17 non-FS GABAergic neurons. The mean magnitude of LTP in the former cell group was larger than that in the latter. The paired-pulse stimulation protocol and coefficient of variation analysis indicated that LTP of excitatory synapses on FS-GABA neurons may be postsynaptic in origin. Filling postsynaptic cells with a Ca2+-chelator blocked the induction of LTP, suggesting an involvement of postsynaptic Ca2+ rise. The developmental analysis of LTP indicated that almost the same magnitude of LTP was induced after postnatal day 17 to the young adulthood, suggesting no age dependence after eye opening. This form of LTP was dependent neither on NMDA receptors nor voltage-gated Ca2+ channels (L and T types). An antagonist for type 5 metabotropic glutamate receptors (mGluR5) blocked this form of LTP, whereas an antagonist for mGluR1 was not effective. An agonist for mGluR1/5 induced potentiation of EPSPs of FS-GABA neurons in concentration- and use-dependent manners. This potentiation and TBS-induced LTP occluded each other. Further pharmacological analyses suggested that this form of LTP at FS-GABA neurons is induced through an activation of mGluR5, which triggers Ca2+ release from internal stores via activations of phospholipase C and inositol triphosphate.
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PMID:Metabotropic glutamate receptor type 5-dependent long-term potentiation of excitatory synapses on fast-spiking GABAergic neurons in mouse visual cortex. 1823

Estrogens are involved in the hypothalamic control of multiple homeostatic functions including reproduction, stress responses, energy metabolism, sleep cycles, temperature regulation and motivated behaviors. The actions of 17beta-estradiol (E(2)) in the brain have been attributed to the activation of estrogen receptors alpha and beta, as well as G-protein-coupled or other membrane-associated estrogen receptors. Recently, we have identified a putative membrane-associated estrogen receptor that is coupled to desensitization of GABA(B) receptors in guinea pig and mouse hypothalamic neurons including proopiomelanocortin (POMC) neurons. We have synthesized a new nonsteroidal compound, STX, which selectively targets the Galphaq-coupled phospholipase C-protein kinase C-protein kinase A pathway, and have established that STX is more potent than E(2) in mediating this desensitization in an ICI 182,780-sensitive manner in both guinea pig and mouse neurons. Both E(2) and STX are fully efficacious in estrogen receptor alpha, beta knock-out mice. Finally, we observed that the putative membrane-associated estrogen receptor is different from GPR30 in arcuate neurons using whole-cell patch recording in hypothalamic slices from GPR30 knock-out mice. Collectively, these findings suggest that the mER is distinct from ERalpha, ERbeta or GPR30.
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PMID:Modulation of hypothalamic neuronal activity through a novel G-protein-coupled estrogen membrane receptor. 1834 49

In the ventral tegmental area (VTA), progestins facilitate lordosis via rapid actions at membrane dopamine Type 1-like (D(1)) and/or GABA(A) receptors (GBRs), rather than via cognate, intracellular progestin receptors (PRs). Downstream signal transduction pathways involved in these effects were investigated using lordosis as a bioassay. If progestins' actions at D(1) and/or GBRs in the VTA require activation of G-proteins, adenylyl cyclase, cyclic AMP-dependent protein kinase A (PKA), phospholipase C (PLC), and/or PKC, then pharmacologically blocking these pathways would be expected to attenuate progestin-facilitated lordosis and its enhancement by D(1) and GBR activity. Ovariectomized, estradiol-primed rats were infused first with vehicle or signal transduction inhibitor, and second with vehicle, a D(1) or GBR agonist, and then with vehicle or progestins to the VTA. Rats were tested for lordosis following infusions. Results indicated that initiation of G-proteins, adenylyl cyclase, PKA, PLC, or PKC in the VTA is required for rapid effects of progestins through D(1) and/or GBRs to facilitate lordosis. As well, progestins' actions at n-methyl-d-aspartate receptors (NMDARs) may modulate activity at D(1) and/or GBRs and mitogen activated protein kinase (MAPK) may be a common signaling pathway. Findings from a microarray study demonstrated that there was upregulation of genes associated with steroid metabolism, GBRs, D(1), NMDARs and signal transduction factors in the midbrain VTA of naturally receptive mated compared to non-mated rats. Thus, in the VTA, progestins have rapid membrane-mediated actions via D(1), GBRs, NMDARs and their downstream signal transduction pathways.
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PMID:Membrane actions of progestins at dopamine type 1-like and GABAA receptors involve downstream signal transduction pathways. 1834 51

Steroid hormones have pervasive functional effects. Although steroids are generally known to have actions via binding to their cognate steroid receptors, it is becoming clearer that steroids can have non-traditional actions that do not require activation of cognate steroid receptors. We have found that progestogen-facilitated lordosis of rodents is enhanced by activation of dopamine type 1 (D1) or GABA(A) receptors and their downstream effectors, such as second messengers, in the ventral tegmental area (VTA). The role of phospholipase C in these effects is not clear. If progestins' actions through D1 and GABA(A) receptors in the VTA are mediated through PLC, then inhibiting PLC formation in the VTA, via infusions of U73122 (400nM/side), should reduce progestin (5alpha-pregnan-3alpha-ol-20-one; 3alpha,5alpha-THP; 100 or 200ng/side)-facilitated lordosis and its enhancement by D1 (SKF38393; 100ng/side) or GABA(A) (muscimol; 100ng/side) receptor agonists in ovariectomized, estradiol-primed rats. We found that 3alpha,5alpha-THP-, SKF38393-, and muscimol-facilitated lordosis was attenuated by infusions of the PLC inhibitor, U73122, but not vehicle, to the VTA. Thus, progestogens' non-traditional actions in the VTA to enhance lordosis through D1 and/or GABA(A) include activity of PLC.
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PMID:In the ventral tegmental area, progestogens' membrane-mediated actions for lordosis of rats involve the second-messenger phospholipase C. 1867 54

Whereas the entorhinal cortex (EC) receives profuse serotonergic innervations from the raphe nuclei in the brain stem and is critically involved in the generation of temporal lobe epilepsy, the function of serotonin (5-hydroxytryptamine, 5-HT) in the EC and particularly its roles in temporal lobe epilepsy are still elusive. Here we explored the cellular and molecular mechanisms underlying 5-HT-mediated facilitation of GABAergic transmission and depression of epileptic activity in the superficial layers of the EC. Application of 5-HT increased sIPSC frequency and amplitude recorded from the principal neurons in the EC with no effects on mIPSCs recorded in the presence of TTX. However, 5-HT reduced the amplitude of IPSCs evoked by extracellular field stimulation and in synaptically connected interneuron and pyramidal neuron pairs. Application of 5-HT generated membrane depolarization and increased action potential firing frequency but reduced the amplitude of action potentials in presynaptic interneurons suggesting that 5-HT still increases GABA release whereas the depressant effects of 5-HT on evoked IPSCs could be explained by 5-HT-induced reduction in action potential amplitude. The depolarizing effect of 5-HT was mediated by inhibition of TASK-3 K(+) channels in interneurons and required the functions of 5-HT(2A) receptors and Galpha(q/11) but was independent of phospholipase C activity. Application of 5-HT inhibited low-Mg(2+)-induced seizure activity in slices via 5-HT(1A) and 5-HT(2A) receptors suggesting that 5-HT-mediated depression of neuronal excitability and increase in GABA release contribute to its anti-epileptic effects in the EC.
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PMID:Serotonin increases GABA release in rat entorhinal cortex by inhibiting interneuron TASK-3 K+ channels. 1868 3

To investigate whether GABA/progesterone (P(4)) stimulates PPI breakdown and its role in the acrosome reaction (AR), spermatozoa of guinea pig were preincubated in MCM-LCa(2+) for 5.5 h and then labeled with [(32)P]pi for 1 h. Samples were washed through a three-step gradient Percoll, adjusted to 5x10(7) cells/mL and exposed to 2 mmol/L Ca(2+), 5 micromol/L GABA, 10 micromol/L P(4) and other agents. Lipids were separated by t.l.c. and radioactivity in spots determined by scintillation counting. The AR was assessed by phase-contrast microscopy. The results showed that (i) when spermatozoa were treated with GABA,(32)P-label diminished rapidly in phosphatidylinositol 4, 5-bisphosphate (PIP(2)), phosphatidylinositol 4-phosphate (PIP), and increased in phosphatidic acid (PA). The loss of label from PPI was almost completed by 10 min. The time-course of the AR was much slower than PPI when spermatozoa reached a maximal response by 15 min; (ii) the pattern of PPI hydrolysis and stimulation of AR was similar for the three agonists tested; their potency followed the order A23187>progesterone> or =GABA; (iii) GABA-induced PIP(2) hydrolysis and rise in PA and the AR were prevented by inclusion of 10 mmol/L neomycin; (iv) the loss of PIP(2) labeling and the increase in PA labeling abolished when spermatozoa were exposed to EGTA or Ca(2+) channel blocker. These results indicate that GABA or P(4)-induced PPI breakdown is an important and essential event in the series of changes to membrane fusion during the AR of guinea pig spermatozoa and this effect is mediated via calcium by activation of phosphatidylinositol-specific phospholipase C.
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PMID:GABA/progesterone-induced polyphosphoinositide (PPI) breakdown and its role in the acrosome reaction of guinea pig spermatozoa in vitro. 1872 15


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