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 AP4 (2-amino-4-phosphonobutyrate) receptor is a presynaptic glutamate receptor that inhibits transmitter release via an unknown mechanism. We examined the action of L-AP4 on voltage-dependent calcium currents and excitatory synaptic transmission on cultured olfactory bulb neurons using whole-cell voltage-clamp methods. In neurons dialyzed with GTP, L-AP4 inhibited high-threshold calcium currents evoked in barium solutions. The inhibition was irreversible in the presence of GTP-gamma-S and blocked by removing intracellular Mg2+ or by preincubation with pertussis toxin (PTX), consistent with the involvement of a PTX-sensitive G-protein. Dialysis with staurosporine or buffering of intracellular calcium to pCa less than 8 did not block the action of L-AP4, suggesting that protein phosphorylation or release of intracellular calcium stores was not involved in calcium current inhibition under these experimental conditions. PTX also blocked the L-AP4-induced inhibition of monosynaptic EPSPs evoked by intracellular stimulation of cultured mitral cells. These results suggest that the presynaptic AP4 receptor is a G-protein-coupled glutamate receptor, and that inhibition of calcium influx by a membrane-delimited action of a G-protein may account for L-AP4-induced presynaptic inhibition.
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PMID:L-AP4 inhibits calcium currents and synaptic transmission via a G-protein-coupled glutamate receptor. 131 54

1. Intracellular microelectrode recordings were used to study the cellular location, pharmacology, and mechanism of action of gamma-aminobutyric acidB (GABAB) receptors on pyramidal cells and presynaptic axonal endings in area CA3 of organotypic hippocampal slice cultures. 2. Baclofen (bath applied at 10 microM) caused a 10-15 mV hyperpolarization of CA3 cells and a 75-100% decrease in the amplitude of excitatory and inhibitory postsynaptic potentials (EPSPs and IPSPs). Baclofen reduced the amplitude of monosynaptic IPSPs elicited in the presence of excitatory amino acid receptor antagonists, as well as the amplitude of EPSPs elicited after blocking GABAA receptors and reducing subsequent epileptic bursts with excitatory amino acid receptor antagonists. These data indicate that GABAB receptors are located on both excitatory and inhibitory presynaptic elements. 3. The GABAB receptor antagonist CGP 35 348 blocked the postsynaptic action of baclofen, the late IPSP, and the reduction of EPSPs and monosynaptic IPSPs by baclofen. 3-Aminopropylphosphinic acid (3-APA) mimicked all the pre- and postsynaptic actions of baclofen, and its effects were fully antagonized by CGP 35 348. 4. Incubation of cultures with pertussis toxin (500 ng/ml for 48 h) prevented both the postsynaptic hyperpolarization and the block of monosynaptic IPSPs induced by baclofen. The action of baclofen on isolated EPSPs, however, was not affected by pertussis toxin treatment. Stimulation of protein kinase C with phorbol ester (phorbol 12, 13 dibutyrate, 1 microM for 10 min) reduced all pre- and postsynaptic effects of GABAB receptor activation. 5. Barium (bath applied at 1 mM) prevented both the baclofen-induced hyperpolarization of pyramidal cells and the block of monosynaptic IPSPs by baclofen. In the presence of barium, however, baclofen was fully capable of blocking EPSPs. 6. We conclude that pre- and postsynaptic GABAB receptors are pharmacologically indistinguishable, at present, and that all actions of GABAB receptors are inhibited by stimulation of protein kinase C. Both the postsynaptic action of baclofen and the block of GABA release from interneurons are mediated by pertussis toxin-sensitive G proteins which can be inactivated by stimulation of protein kinase C. Baclofen acts at postsynaptic sites and on the axon terminals of inhibitory interneurons by activating the same barium-sensitive K+ conductance. GABAB receptors on excitatory axons must, however, work through some other mechanism.
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PMID:Comparison of the actions of baclofen at pre- and postsynaptic receptors in the rat hippocampus in vitro. 132 19

1. Intracellular microelectrode recordings were used to study the cellular location, the receptor pharmacology, and the mechanism of action of adenosine on pyramidal cells and presynaptic axonal endings in area CA3 of organotypic hippocampal slice cultures. 2. Adenosine (bath applied at 50 microM) caused a 10-15 mV hyperpolarization of CA3 cells, as well as a 75-100% decrease in the amplitude of excitatory and polysynaptic inhibitory postsynaptic potentials (EPSPs and IPSPs). Adenosine had no effect on the amplitude of monosynaptic IPSPs elicited in the presence of excitatory amino acid receptor antagonists, but did reduce the amplitude of isolated EPSPs, elicited after blocking GABAA receptors and reducing subsequent epileptic bursts with excitatory amino acid receptor antagonists. These data indicate that adenosine receptors are located on excitatory, but not inhibitory, presynaptic elements. 3. The A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, bath applied at 200 nM) blocked the pre- and postsynaptic actions of adenosine. DPCPX had no effect on the amplitude of control synaptic responses, suggesting that there is no tonic activation of adenosine receptors in hippocampal slice cultures under control conditions. The A1 receptor agonists R-N6-phenylisopropyladenosine (R-PIA) mimicked all pre- and postsynaptic actions of adenosine. 4. Pertussis toxin pretreatment (500 ng/ml for 48 h) prevented adenosine from activating postsynaptic K+ conductance, but not from inhibiting EPSPs. In contrast, stimulation of protein kinase C with phorbol ester (phorbol 12, 13-dibutyrate, 1 microM for 10 min) reduced the presynaptic, but not the postsynaptic, actions of adenosine. 5. Barium (bath applied at 1 mM) blocked the adenosine-activated K+ conductance, but not the inhibition of isolated EPSPs by adenosine. 6. Adenosine at 0.03-1 microM reduced the frequency of, or blocked, spontaneous epileptiform bursting produced by bicuculline. DPCPX (200 nM) increased the rate of spontaneous bursting, consistent with a tonic activation of adenosine receptors during hyperactivity, and led to the development of prolonged ictal-like bursts, suggesting that the endogenous release of adenosine may contribute to the termination of epileptic bursts. 7. We conclude that adenosine acts at pre- and postsynaptic receptors which are pharmacologically indistinguishable. Postsynaptically, adenosine increases a barium-sensitive K+ conductance via a pertussis toxin-sensitive GTP-binding protein. The presynaptic action of adenosine must, however, be mediated by some other mechanism.
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PMID:Comparison of the actions of adenosine at pre- and postsynaptic receptors in the rat hippocampus in vitro. 140 15

The whole-cell patch clamp technique was used to test whether intracellular application of G-protein activators affect ionic currents in murine macrophages. Both the J774.1 macrophage-like cell line and primary bone marrow derived macrophages were used. Cells were bathed in Na Hanks' solution and intracellularly dialyzed (via the patch pipette) with K Hanks (145 mM KCl, < 100 nM Ca) plus or minus the G-protein activators GTP gamma S (10 microM), GppNHp (10 microM), or AIF4- (200 microM AlCl3 + 5 mM KF). In the absence of G-protein activators, only two K currents, an inwardly rectifying K current (Kir) and an outward, inactivating K current (Ko) were observed. In the presence of protein activators, two effects were observed: (i) the Kir conductance, which is stable for up to 30 min under control conditions, decayed twice as fast and (ii) an outwardly rectifying, noninactivating current appeared. The induced outward current appeared < 2 min after attaining the whole-cell patch clamp configuration. The current could be distinguished from the Kir and Ko currents on the basis of its direction of rectification (outward), barium sensitivity (> 1 mM), and kinetics (no time-dependent inactivation). Intracellular application of GTP (500 microM), GDP (500 microM), cAMP (100 microM + 0.5 mM ATP), or IP3 (20 microM) did not induce the current; 100 microM ATP gamma S activated a half-maximal amount of current. Induction of outward current by 10 microM GTP gamma S could be prevented by pre-exposing cells to pertussis toxin but not cholera toxin. This current is K selective since (i) its induction was accompanied by hyperpolarization of the cell toward EK, even after Kir had "washed out", (ii) it was present after > 90% of both intracellular and extracellular Cl were replaced by isethionate, and (iii) the induced outward conductance was absent when Ki was completely replaced by Cs, and was reduced by approximately 1/3 when [K]i was reduced by 1/3. Quinidine (1 mM) and 4-aminopyridine (10 mM) inhibited the current, but apamin (1 microM) and charybdotoxin (1 microM) did not.
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PMID:G-protein activators induce a potassium conductance in murine macrophages. 149 29

1. The mechanism by which cloned m1 and m3 muscarinic receptor subtypes activate Ca2+-dependent channels was investigated with whole-cell and cell-attached patch-clamp recording techniques and with Fura-2 Ca2+ indicator dye measurements in cultured A9 L cells transfected with rat m1 and m3 cDNAs. 2. The Ca2+-dependent K+ and Cl- currents induced by muscarinic receptor stimulation were dependent on GTP. Responses were reduced when GTP was excluded from the intracellular recording solution or when GDP-beta-S was added. Intracellular GTP-gamma-S activated spontaneous fluctuations and permitted only one acetylcholine-(ACh) induced current response. These results implicate GTP-binding proteins (G protein) in the signal transduction pathway. This G protein is probably not pertussis toxin-sensitive as the ACh-induced electrical response was not abolished by pertussis toxin treatment. 3. Cell-attached single-channel recordings revealed activation of ion channels within the patch during application of ACh outside the patch, implying that second messengers might be involved in the ACh-induced response. Two types of K+ channel were activated, a discrete channel of 36 pS and channel activity calculated to be about 5 pS. 4. Application of 8-bromo cyclic AMP or 1-oleoyl-1,2-acetylglycerol (OAG) produced no electrical response and did not affect the ACh-induced responses. Phorbol myristic acetate (PMA) evoked no electrical response, but reduced the ACh-induced responses. 5. Inclusion of inositol 1,4,5-trisphosphate (IP3) in the intracellular pipette solution activated outward currents at -50 mV associated with an increase in conductance. The IP3-induced current response reversed polarity at -65 mV and showed a dependence on K+. Increasing the intracellular free Ca2+ concentration ([Ca2+]i) from 20 nM to 1 microM also induced an outward current response associated with an increase in conductance. Inclusion of inositol 1,3,4,5-tetrakisphosphate (IP4) in the intracellular solution had no effect on the A9 L cells. 6. Fura-2 measurements revealed ACh-induced increases in Cai2+. The Ca2+ responses were abolished by atropine showing that they were muscarinic in nature. Removal of extracellular Ca2+ did not affect the initial ACh-induced increase in Cai2+ but subsequent Cai2+ responses to ACh were depressed, suggesting depletion of Ca2+ intracellular stores. Residual though small responses continued to be elicited by ACh. Barium (5 mM) had little effect and cobalt slightly reduced the ACh-induced Ca2+ response. 7. The ACh-induced currents recorded at -50 mV were unaffected by removal of extracellular Ca2+.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Inositol trisphosphate mediates cloned muscarinic receptor-activated conductances in transfected mouse fibroblast A9 L cells. 169 2

1. Membrane currents were recorded by a patch-clamp pipette technique in cultured cells from rat portal vein using the whole-cell mode. 2. Noradrenaline (NA, 10(-5) M) and phorbol-12,13-dibutyrate (PDBu, 10(-7) M) produced an increase in voltage-dependent inward current carried by barium (5 mM), but their effects were not additive. Calcium-activated chloride current was evoked by NA but not by PDBu. 3. The NA-induced increase in peak voltage-dependent inward current was inhibited by intracellular application of GDP-beta-S (10(-3) M) while the effect of PDBu was unchanged. GDP-beta-S blocked the NA-induced chloride current but had no effect on the caffeine-induced chloride current. 4. Inclusion of GTP-gamma-S (10(-5)-10(-4) M) in the pipette solution increased the voltage-dependent inward current and inhibited the NA- or PDBu-induced increase in peak current. GTP-gamma-S potentiated the effect of NA on calcium-activated chloride current. At higher concentrations (10(-3) M), GTP-gamma-S activated the chloride current and prevented the effects of NA or caffeine on this current. 5. The combination of 10(-5) M-aluminium chloride and 10(-2) M-sodium fluoride had an effect similar to that of high concentrations of GTP-gamma-S on both inward current and calcium-activated chloride current. In contrast, arachidonic acid (10(-3) M) had no effect on calcium and chloride conductances activated by NA. 6. Cells responded normally to NA after pre-treatment for 4-30 h with 10 micrograms ml-1 pertussis toxin (PTx). 7. It is concluded that the stimulation of calcium and chloride conductances by NA is mediated through activation of a PTx-insensitive GTP-binding protein. This effect may involve activation of phospholipase C enzyme and production of both D-myo-inositol 1,4,5-trisphosphate which depletes calcium stores and diacylglycerol which activates protein kinase C.
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PMID:GTP-binding proteins mediate noradrenaline effects on calcium and chloride currents in rat portal vein myocytes. 170 Jan 11

Thrombin stimulates phosphoinositide hydrolysis and increases cytosolic calcium in several types of cells. To determine whether thrombin exerts similar stimulatory actions in the heart and whether this mechanism is linked to changes in cardiac electrical activity, the effects of thrombin on several biochemical and electrophysiological parameters were examined. In neonatal rat ventricular myocyte cultures freed of fibroblast contamination by irradiation, thrombin rapidly induced the breakdown of phosphoinositides. Formation of inositol trisphosphate was detectable within 5 seconds and was followed by the sequential accumulation of inositol bisphosphate and inositol monophosphate. The effect of thrombin to stimulate phosphoinositide hydrolysis was inhibited by hirudin, but not by propranolol, prazosin, or pretreatment with pertussis toxin. The inositol phospholipid response was unassociated with changes in intracellular cAMP levels. To determine the electrophysiological effects of thrombin, we used microelectrode techniques to study canine Purkinje fibers. Thrombin increased the beating rate of fibers depolarized using barium, but not those at normal maximal diastolic potential. In addition, thrombin prolonged the action potential duration in fibers driven at a constant cycle length. This response was inhibited by hirudin and nisoldipine, but not by propranolol, prazosin, or pretreatment with pertussis toxin. Thrombin also augmented cesium-induced early afterdepolarizations. Using the fluorescent calcium indicator fura-2, we demonstrated that thrombin increased the beating rate, diastolic calcium, and peak systolic calcium of spontaneously contracting cultured ventricular myocytes. Cytosolic calcium also increased in both rat ventricular myocytes and canine Purkinje myocytes that were electrically driven at a constant basic cycle length, indicating that thrombin modulates cellular calcium metabolism independent of its actions to enhance automaticity. Taken together, these findings demonstrate several novel biological actions of thrombin in the mammalian heart that may be functionally related. The actions of thrombin to enhance automaticity and prolong repolarization may contribute to the electrical abnormalities observed in the setting of myocardial ischemia and infarction.
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PMID:Thrombin modulates phosphoinositide metabolism, cytosolic calcium, and impulse initiation in the heart. 185 Mar 29

Progesterone causes natriuresis, an effect largely attributed to displacement of aldosterone from its receptor. The present study, however, demonstrates that progesterone (0.1, 1, and 10 mumol/1, respectively) also causes a rapid, fully reversible depolarization of Madin-Darby canine kidney (MDCK) cells (by 1.3 +/- 0.5, 4.1 +/- 0.7 and 12.3 +/- 1.5 mV, respectively). 17 alpha-Hydroxyprogesterone and dihydroxytestosterone are, by two orders of magnitude, less effective, whereas cholesterol, aldosterone, hydrocortisone, and estradiol (each up to 10 mumol/l) did not significantly alter the potential difference across the cell membrane. The effect of progesterone is blunted by antiprogestogen RU 486 (5 mumol/l). The progesterone-induced depolarization is paralleled by a decrease of potassium selectivity and an increase of cell membrane resistance and is abolished in the presence of the potassium channel blocker barium (10 mmol/l), as well as in the presence of 40 mmol/l potassium in the extracellular fluid. Neither removal of extracellular chloride or bicarbonate nor amiloride, ouabain, or pretreatment with pertussis toxin abolish the depolarizing effect of 5 mumol/l progesterone. In conclusion, acute administration of progesterone depolarizes MDCK cells by decreasing the potassium conductance of the cell membrane.
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PMID:Progesterone inhibits K conductance in plasma membrane of cultured renal epitheloid MDCK cells. 203 30

1. Intracellular recordings were obtained from submucous plexus neurones of the guinea-pig caecum. 2. The resting membrane conductance displayed two types of inward rectification: one which developed at potentials more negative than -70 mV, and another that occurred at potentials more negative than the potassium equilibrium potential. The former inward rectification was blocked by extracellular caesium (Cs+; 1-2 mM) and the latter was blocked by Cs+ (1-2 mM) or barium (Ba2+; 30-100 microM). 3. The noradrenaline-induced current measured by subtraction of the current-voltage (I-V) relation before and after adding the agonist also showed an inward rectification around the resting potential. Ba2+ (30-100 microM) blocked both the outward and inward current induced by noradrenaline. The noradrenaline current was not affected by Cs+ (1-2 mM). Both the slow IPSP and the slow IPSC (inhibitory postsynaptic current) were reduced by Ba2+, but not by Cs+. 4. During the intracellular injection of guanosine 5'-O-(3-thiotriphosphate) (GTP-gamma-S), multiple repetitive stimulation or repeated applications of noradrenaline produced irreversible membrane hyperpolarizations with a decreased membrane input resistance, until the membrane had approached the potassium equilibrium potential. 5. Pertussis toxin (1-40 micrograms/ml) abolished both the slow IPSP and the noradrenaline hyperpolarization without affecting the nicotinic fast EPSP or the slow EPSP. 6. Superfusion with a Ca(2+)-free, high-Mg2+ (12 mM) solution caused a membrane depolarization associated with an increased input resistance. It eliminated the Ca2+ spikes, the slow after-hyperpolarizations following the spikes, and the synaptic potentials within 3 min. Prolonged exposure (longer than 20 min) to this solution resulted in a progressive decline of the noradrenaline hyperpolarization. 7. Intracellular injection of ethylene glycol-bis(beta-aminoethylether)N,N,N',N'-tetraacetic acid (EGTA) reduced the slow IPSP and the noradrenaline hyperpolarization. Superfusion with a membrane-permeable Ca2+ chelator, 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, tetraacetoxymethyl ester (BAPTA/AM; 10-200 microM) reduced the noradrenaline hyperpolarization. 8. Procaine reversibly reduced the slow IPSP and noradrenaline hyperpolarization without affecting the fast EPSP or slow EPSP at concentrations up to 300 microM.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Mechanisms underlying intracellular signal transduction of the slow IPSP in submucous neurones of the guinea-pig caecum. 206 48

We compared the effects of a series of di- and trivalent cations on various aspects of parathyroid function to investigate whether these polyvalent cations act on the parathyroid cell through a similar mechanism. Like high extracellular concentrations of Ca2+, high levels of barium (Ba2+), strontium (Sr2+), gadolinium (Gd3+), europium (Eu3+), terbium (Tb3+), and ytterbium (Yb3+) [corrected] each inhibited low calcium-stimulated PTH release and showed IC50 values (the concentration producing half of the maximal inhibitory effect) of 1.12 mM, 1.18 mM, 2.2 microM, 2.5 microM, 0.89 microM, and 15 microM, respectively. The inhibitory effects of both divalent (Ca2+ and Ba2+) and trivalent (Gd3+) cations were reversible by 76-100% after removal of the cation, suggesting that the polyvalent cation-mediated reduction in PTH release was not due to nonspecific toxicity. The same di- and trivalent cations produced an 80-90% decrease in agonist-stimulated cAMP accumulation with a similar order of potency as for their effects on PTH release. Preincubation overnight with pertussis toxin totally prevented the inhibitory effects of the trivalent cations on cAMP accumulation. The same di- and trivalent cations also increased the accumulation of inositol monophosphate, inositol bisphosphate, and inositol trisphosphate. Their effects on this parameter differed from those on PTH release and cAMP accumulation in several respects. First, Ba2+ and Sr2+, rather than being equipotent with Ca2+, were about 2-fold less potent in increasing the levels of inositol phosphates. Second, the trivalent cations were 5-50-fold less potent in raising inositol phosphates than in modulating PTH release and cAMP accumulation, and all were nearly equipotent. These results show that trivalent cations of the lanthanide series mimic the actions of divalent cations on several aspects of parathyroid function, and likely do so by interacting with the cell surface "Ca2(+)-receptor-like mechanism" through which extracellular Ca2+ has been postulated to act. The pharmacology of the effects of these polyvalent cations on cAMP and PTH release are similar and differ from that for their actions on inositol phosphate metabolism, raising the possibility that there might be more than one form of the putative Ca2+ receptor.
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PMID:A comparison of the effects of divalent and trivalent cations on parathyroid hormone release, 3',5'-cyclic-adenosine monophosphate accumulation, and the levels of inositol phosphates in bovine parathyroid cells. 216 4


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