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)

We co-immunoprecipitated the Ca(2+)-sensing receptor (CaR) and type B gamma-aminobutyric acid receptor (GABA-B-R) from human embryonic kidney (HEK)-293 cells expressing these receptors and from brain lysates where both receptors are present. CaRs extensively co-localized with the two subunits of the GABA-B-R (R1 and R2) in HEK-293 cell membranes and intracellular organelles. Coexpressing CaRs and GABA-B-R1s in HEK-293 cells suppressed the total cellular and cell surface expression of CaRs and inhibited phospholipase C activation in response to high extracellular [Ca(2+)] ([Ca(2+)](e)). In contrast, coexpressing CaRs and GABA-B-R2s enhanced CaR expression and signaling responses to raising [Ca(2+)](e). The latter effects of the GABA-B-R2 on the CaR were blunted by coexpressing the GABA-B-R1. Coexpressing the CaR with GABA-B-R1 or R2 enhanced the total cellular and cell surface expression of the GABA-B-R1 or R2, respectively. Studies with truncated CaRs indicated that the N-terminal extracellular domain of the CaR participated in the interaction of the CaR with the GABA-B-R1 and R2. In cultured mouse hippocampal neurons, CaRs co-localized with the GABA-B-R1 and R2. CaRs and GABA-B-R1s also co-immunoprecipitated from brain lysates. The expression of the CaR was increased in lysates from GABA-B-R1 knock-out mouse brains and in cultured hippocampal neurons with their GABA-B-R1 genes deleted in vitro. Thus, CaRs and GABA-B-R subunits can form heteromeric complexes in cells, and their interactions affect cell surface expression and signaling of CaR, which may contribute to extracellular Ca(2+)-dependent receptor activation in target tissues.
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PMID:Complex formation with the Type B gamma-aminobutyric acid receptor affects the expression and signal transduction of the extracellular calcium-sensing receptor. Studies with HEK-293 cells and neurons. 1759 80

Extracellular calcium-sensing receptors (CaRs) and metabotropic or type B gamma-aminobutyric acid receptors (GABA-B-Rs), two closely related members of family C of the G protein-coupled receptor superfamily, dimerize in the formation of signaling and membrane-anchored receptor complexes. We tested whether CaRs and two GABA-B-R subunits (R1 and R2) are expressed in mouse growth plate chondrocytes (GPCs) by PCR and immunocytochemistry and whether interactions between these receptors influence the expression and function of the CaR and extracellular Ca(2+)-mediated cell differentiation. Both CaRs and the GABA-B-R1 and -R2 were expressed in the same zones of the growth plate and extensively colocalized in intracellular compartments and on the membranes of cultured GPCs. The GABA-B-R1 co-immunoprecipitated with the CaR, confirming a physical interaction between the two receptors in GPCs. In vitro knockout of GABA-B-R1 genes, using a Cre-lox recombination strategy, blunted the ability of high extracellular Ca(2+) concentration to activate phospholipase C and ERK1/2, suppressed cell proliferation, and enhanced apoptosis in cultured GPCs. In GPCs, in which the GABA-B-R1 was acutely knocked down, there was reduced expression of early chondrocyte markers, aggrecan and type II collagen, and increased expression of the late differentiation markers, type X collagen and osteopontin. These results support the idea that physical interactions between CaRs and GABA-B-R1s modulate the growth and differentiation of GPCs, potentially by altering the function of CaRs.
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PMID:Type B gamma-aminobutyric acid receptors modulate the function of the extracellular Ca2+-sensing receptor and cell differentiation in murine growth plate chondrocytes. 1761 48

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

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian central nervous system and exerts its actions via both ionotropic (GABA(A)) and metabotropic (GABA(B)) receptors. The GABA(B) receptor is a dimer composed of R1 and R2 components and classically couples to the heterotrimeric G(i) protein. In addition to their location on neurons, GABA and functional GABA(B) receptors have been detected in peripheral tissue such as airway smooth muscle. We questioned whether airway epithelium expresses receptors that could respond to GABA. We detected the mRNA encoding multiple-splice variants of the GABA(B)R1 and GABA(B)R2 in total RNA isolated from native human and guinea pig airway epithelium and human airway epithelial cell lines (BEAS-2B and H441). Immunoblots identified the GABA(B)R1 and GABA(B)R2 proteins in both guinea pig airway epithelium and BEAS-2B cells. The expression of GABA(B)R1 protein was immunohistochemically localized to basal mucin-secreting and ciliated columnar epithelial cells in guinea pig trachea. Baclofen inhibited adenylyl cyclase activity, induced ERK phosphorylation and cross-regulated phospholipase C, leading to increased inositol phosphates in BEAS-2B cells in a pertussis toxin-sensitive manner, implicating G(i) protein coupling. Thus, these receptors couple to G(i) and cross-regulate the phospholipase C/inositol phosphate pathway. The second messengers of these pathways, cyclic AMP and calcium, play pivotal roles in airway epithelial cell primary functions of mucus clearance. Furthermore, the enzyme that synthesizes GABA, glutamic acid decarboxylase (GAD65/67), was also localized to airway epithelium. GABA may modulate an uncharacterized signaling cascade via GABA(B) receptors coupled to G(i) protein in airway epithelium.
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PMID:Functional expression of GABAB receptors in airway epithelium. 1840 80


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