Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The inhibition of voltage-activated Ca2+ channel currents by cortisol (hydrocortisone), the principal glucocorticoid in man and guinea pig, was examined in freshly dissociated pyramidal neurons from the adult guinea pig hippocampal CA1 region using whole-cell voltage-clamp recordings. Steady-state inhibition by cortisol of the peak Ca2+ channel current evoked by depolarization from -80 to -10 mV increased in a concentration-dependent fashion, with a maximal inhibition of 63 +/- 4% of the total current at 100 microM. Cortisone had a maximal 17 +/- 2% inhibition at 10 microM. Corticosterone and the metabolite allotetrahydrodeoxycorticosterone exhibited a plateau of inhibition of around 15% and 25%, respectively, between 10 pM and 100 nM; both compounds continued to inhibit at concentrations > 10(-7) M. Analysis of tail currents at -80 mV showed that cortisol and corticosterone had no effect on the voltage-dependent activation or deactivation of the Ca2+ channel current. However, cortisol slowed the activation of the current. Cortisol inhibited both the N-type or omega-conotoxin (CgTX)-sensitive, and the L-type or nifedipine (NIF)-sensitive Ca2+ channel current but had no effect on the CgTX/NIF-insensitive Ca2+ channel current. In neurons isolated from pertussis toxin (PTX)-treated animals, the cortisol inhibition was significantly diminished. Intracellular dialysis with GDP-beta-S (500 microM) or with the specific inhibitors of protein kinase C (PKC), the pseudosubstrate PKC inhibitor (PKCI 19-31) (2 microM) and bisindolylmaleimide (BIS) (1 microM) significantly diminished the cortisol inhibition of the Ca2+ channel current. The specific inhibitor of cAMP-dependent protein kinase (PKA) inhibitor, Rp-cAMPS (100 microM) had no effect.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cortisol inhibition of calcium currents in guinea pig hippocampal CA1 neurons via G-protein-coupled activation of protein kinase C. 782 88

The inhibition of Ca2+ channel currents by endogenous brain steroids was examined in freshly dissociated pyramidal neurons from the adult guinea pig hippocampal CA1 region. The steady-state inhibition of the peak Ca2+ channel current evoked by depolarizing steps from -80 to -10 mV occurred in a concentration-dependent manner with the following IC50 values: pregnenolone sulfate (PES), 11 nM; pregnenolone (PE), 130 nM; and allotetrahydrocorticosterone (THCC), 298 nM. THCC, PE, and PES depressed a fraction of the Ca2+ channel current with a maximal inhibition of 60% of the total current. However, substitution of an acetate group for the sulfate group on PES resulted in a complete loss of activity. Progesterone had no effect (4% inhibition at 100 microM). Intracellular dialysis of PES had no effect on the Ca2+ current; concomitant extracellular perfusion of PES showed normal inhibitory activity, suggesting that the steroid binding site can only be accessed extracellularly. Analysis of tail currents at -80 mV demonstrated that THCC and PES slowed the rate of Ca2+ current activation and deactivation with no change in the voltage dependence of activation. Inhibition of the Ca2+ channel current by THCC and PES was voltage dependent. THCC primarily inhibits the omega-conotoxin (CgTX)-sensitive or N-type Ca2+ channel current. PE was nonselective in inhibiting both the CgTX- and the nifedipine (NIF)-sensitive Ca2+ channel current. These neurosteroids had no effect on the CgTX/NIF-insensitive current. In neurons isolated from pertussis toxin (PTX)-treated animals by chronic intracerebroventricular infusion (1000 ng/24 hr for 48 hr), the Ca2+ channel current inhibition by PES, PE, and THCC was significantly diminished. Intracellular dialysis with GDP-beta-S (500 microM) also significantly diminished the neurosteroid inhibition of the Ca2+ channel current. Intracellular dialysis with the general kinase inhibitors H-7 (100 microM), staurosporine (400 nM), and a 20 amino acid protein kinase inhibitor (1 microM) also significantly prevented the THCC and PES inhibition of the Ca2+ channel current. Intracellular dialysis with the more specific inhibitors of protein kinase C (PKC), the pseudosubstrate inhibitor (PKCI 19-36) (1-2 microM) and bisindolylmaleimide (1 microM) significantly diminished the THCC and PE inhibition of the Ca2+ channel current. Rp- cAMP (100 microM), a specific inhibitor of cAMP-dependent protein kinase (PKA), had no effect on the THCC and PE inhibition of the Ca2+ current.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Neurosteroids modulate calcium currents in hippocampal CA1 neurons via a pertussis toxin-sensitive G-protein-coupled mechanism. 815 51

1. The effects of the selective thromboxane A2 (TXA2) receptor agonist I-BOP on neuronal excitability and synaptic transmission were studied in the CAl neurones of rat hippocampal slices by an intracellular recording technique. 2. Superfusion of I-BOP (0.5 microM) resulted in a biphasic change of the excitatory postsynaptic potential (e.p.s.p.), which was blocked by pretreatment with SQ 29548, a specific antagonist of TXA2 receptors. The inhibitory phase of I-BOP on the e.p.s.p. was accompanied by a decrease in neuronal membrane input resistance. 3. The sensitivity of postsynaptic neurones to glutamate receptor agonists, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) or N-methyl-D-aspartate (NMDA), was unchanged by I-BOP (0.5 microM) pretreatment. 4. Bath application of Ba2+ (0.5 mM) prevented both the I-BOP-induced reduction of the neuronal membrane input resistance and the blockade of e.p.s.p. induced by I-BOP. 5. Intracellular dialysis of the hippocampal CA1 neurones with GDP (10 mM) significantly attenuated the I-BOP inhibition of e.p.s.p. and membrane input resistance. Incubation of the slices with either pertussis toxin (PTX, 5 micrograms ml-1 for 12 h) or cholera toxin (CTX, 5 micrograms ml-1 for 12 h) did not affect the biphasic action of I-BOP on the e.p.s.p. or the reduction of membrane input resistance induced by I-BOP. 6. Pretreatment of the slices with the protein kinase C (PKC) inhibitor, NPC-15437 (20 microM), abolished the biphasic modulation by I-BOP (0.5 microM) of the e.p.s.p. Intracellular application of a specific PKC inhibitor, PKCI 19-36 (20 microM), completely inhibited the I-BOP reduction of e.p.s.p. The specific cyclic AMP-dependent protein kinase (PKA) inhibitor, Rp-cyclic adenosine 3',5'-monophosphate (Rp-cyclic AMPS, 25 microM), had no effect on the I-BOP action. 7. In this study we have demonstrated, for the first time, the existence of functional TXA2 receptors in the hippocampus which mediate the effects of a TXA2 agonist on neuronal excitability and synaptic transmission. Activation of the presynaptic TXA2 receptors may stimulate the release of glutamate. Conversely, activation of postsynaptic TXA2 receptors leads to inhibition of synaptic transmission resulting from a decrease in the membrane input resistance of the neurones. The pre- and postsynaptic actions of the TXA2 agonist are both mediated by PTX- and CTX-insensitive G-protein-coupled activation of PKC pathways.
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PMID:Thromboxane A2 agonist modulation of excitatory synaptic transmission in the rat hippocampal slice. 886 65

Application of either acetylcholine (ACh), dopamine (DA), histamine (HA), or Phe-Met-Arg-Phe-NH2 (FMRFamide) induces a K+-current response in the identified neurons of Aplysia under voltage clamp. This type of response is mediated by a pertussis toxin (PTX)-sensitive G-protein, Gi or Go. Extracellular application of 60 microM phorbol dibutyrate (PDBu), an activator of protein kinase C (PKC), to these cells markedly depressed all the K+-current responses to ACh, DA, HA, and FMRFamide. The depressing effect of PDBu lasted for at least 60 min despite continuous washing with the normal perfusing medium. Application of PKC inhibitors such as 100 microM H-7 or 10 microM staurosporine and PKCI(19-31) prior to the application of PDBu significantly decreased the depressing effects of PDBu. In contrast, an intracellular injection of okadaic acid (OA), an inhibitor of protein phosphatase 1 and 2A, significantly augmented the blocking effect of PDBu. Intracellular injection of the PKC catalytic subunit induced a similar depressing effect as observed with PDBu. The dose-response curves obtained with different transmitters all shifted downward after the activation of PKC, but the ED50 of each transmitter remained unchanged. Furthermore, the K+-current responses induced by the intracellular application of GTPgammaS were not depressed at all, even after the receptor-induced K+-current responses of the same cell were markedly depressed. These results strongly suggest that PKC phosphorylated a certain coupling site between the receptor and G-protein, and impaired the signal transduction necessary for triggering the K+-channel opening.
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PMID:Functional uncoupling between the receptor and G-protein as the result of PKC activation, observed in Aplysia neurons. 927 Nov 55