UMLS:C0848283 - FACTA Search

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The role of presynaptic muscarinic receptors in modulating neuromuscular transmission was studied in the isolated sartorius muscle of the frog using electrophysiological techniques. In low calcium solutions muscarine reduced mEPP frequency and the quantal of EPPs. In solutions containing the normal calcium concentration the effect of muscarine on quantal content, but not the effect on mEPP frequency, was somewhat attenuated. Muscarine-induced reductions in the parameters of ACh release were prevented by atropine. Irrespective of the calcium concentration, atropine had no effect on mEPP frequency except where fibres were pretreated with glycerol. In experiments where evoked acetylcholine release was maintained at physiologically relevant levels, atropine had no effect on the quantal content of EPPs evoked at low frequency or on the extent of rundown in trains of EPPs evoked at high frequency.
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PMID:The effects of muscarine and atropine reveal that inhibitory autoreceptors are present on frog motor nerve terminals but are not activated during transmission. 164 71

In a newly synthesized series of DMAE analogues (bis-diethyl analogue of hemicholinium-3), selected chemicals (TL-402 = NAM-242 greater than JGC-VII-110) showed significant protection of mouse lethality after acute toxic doses of paraoxon (in vivo). DMAE and NAM-250 (like hemicholinium-3) showed minimal or no antagonism against paraoxon-induced toxicity in mice. Studies with DMAE analogues demonstrate weak anticholinesterase activity. The pattern for the neuromuscular inhibition of TL-402, NAM-242 and JGC-VII-110 is different from that of hemicholinium-3. LD50 studies identified compounds with less inherent toxicity (TL-402, NAM-242 and JGC-VII-110) and showed significant antagonism in contrast to DMAE and NAM-250. These chemicals (DMAE and NAM-250) are as toxic as the parent compound hemicholinium-3. All compounds in this series showed potent antinicotinic activity in different nicotinic-receptor preparations. The antinicotinic activity correlates with their action on the acetylcholine receptor-ion channel complex at frog neuromuscular junctions (in vitro). Electrophysiological studies demonstrate that the antinicotinic agents significantly depressed both the end plate current (EPC) amplitude and the time constant of decay (tau EPC) at the end plate of frog. In presence of paraoxon, voltage- and concentration-dependent shortening of tau EPC is observed which is more prominent than the decrease of the amplitude of EPC. The antinicotinic agents which showed significant antagonism of paraoxon both in vivo and in vitro (TL-402, NAM-242 and JGC-VII-110) also produced profound tetanic rundown after neurally or ionophoretically evoked EPC. These effects are voltage-dependent. The marked shortening of tau EPC, linear relationship between 1/tau vs DMAE analogue concentrations and potential-dependent tetanic rundown suggest that these analogues produce antagonism of paraoxon primarily by reducing end plate permeability by blocking nicotinic ACh-R associated ion channels in their open form. The antinicotinic activity of these agents is related to acetal or corresponding ether substitution.
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PMID:Mechanism for antagonism of paraoxon by hemicholinium-3 analogues. 196 41

In this study, we examined the relative contribution of the increase in acetylcholine-regulated potassium current (IK ACh) and decrease in calcium current (ICa) to the adenosine (Ado)-induced shortening of action potential duration (APD). In isolated guinea pig atrial myocytes, membrane potentials and currents were measured by the whole cell patch-clamp technique. ICa and IK ACh were individualized by blocking the K currents with Cs+ and ICa with Cd2+. The effects of Ado on membrane potential and currents were concentration dependent. Ado (10 microM) shortened APD at 0 mV and at 90% of repolarization (APD0,90) to 7 +/- 1 and 26 +/- 6 ms from control values of 23 +/- 3 and 89 +/- 6 ms, respectively. Concomitant with the changes in APD, Ado decreased ICa from -9.2 +/- 1.3 to -6.8 +/- 10 microA/microF (26% decrease) but increased IK ACh from +3.5 +/- 0.5 to +7.8 +/- 0.8 microA/microF (123% increase). When rundown of ICa was taken into account, the maximum decrease in ICa caused by Ado was 12%. The effect of Ado on ICa and IK ACh was not altered by treatment of the cells with either Cs+ or Cd2+. The shortening of ADP0,90 strongly correlated with the increase in IK ACh but minimally with the decrease in ICa. A 22% reduction in ICa caused by lowering extracellular Ca2+ concentration ([Ca2+]o) from 3.6 to 1.8 mM was associated with an 11 and 14% shortening of APD0 and APD90, respectively. In the same myocytes an 18% decrease in ICa by 10 microM Ado reduced APD0 and APD90 by 58 and 61%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Adenosine-induced changes in atrial action potential: contribution of Ca and K currents. 233 Sep 94

The novel tricyclic alkaloid, gephyrotoxin ( GyTX ), found in the skin secretions of the frog Dendrobates histrionicus , potentiates and blocks the indirectly elicited muscle twitch in a concentration-dependent manner. GyTX prolongs the falling phase of the muscle action potential and decreases delayed rectification, supporting the idea that the alkaloid blocks the voltage-sensitive potassium conductance of the electrically excitable membrane. The peak amplitude of the end-plate currents (EPC) and miniature end-plate currents ( MEPC ) were depressed, but no significant deviation from linearity relative to control was seen in the current-voltage relationship. The decay time constant of the EPC (tau EPC) was markedly shortened by GyTX , the effect being greater at 10 degrees than at 22 degrees. The relationship between the log of tau EPC and membrane potential disclosed a linear relationship at all concentrations tested, but a progressive loss of voltage sensitivity of tau EPC was seen when GyTX concentrations were increased. Also, the plot of 1/tau EPC against GyTX concentration revealed a linear relationship. The lack of voltage and time dependence suggests that GyTX has little effect on the ACh receptor-ionic channel complex in the closed conformation. Single-channel conductance studied by means of fluctuation analysis did not change after GyTX application, but the channel lifetime decreased by about 40% at clamp potentials of -105 mV and at a toxin concentration of 7.5 microM. Repetitive nerve stimulation led to a pronounced " rundown " in the EPCs which was frequency-dependent. These findings were taken as evidence that GyTX interacts with the acetylcholine receptor complex, causing a blockade of its channel mainly in the open conformation.
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PMID:Interactions of gephyrotoxin with the acetylcholine receptor-ionic channel complex. I. Blockade of the ionic channel. 632 64

The diversity of neuronal nicotinic receptors (nAChRs) in addition to their possible involvement in such pathological conditions as Alzheimer's disease have directed our research towards the characterization of these receptors in various mammalian brain areas. Our studies have relied on electrophysiological, biochemical, and immunofluorescent techniques applied to cultured and acutely dissociated hippocampal neurons, and have been aimed at identifying the various subtypes of nAChRs expressed in the mammalian central nervous system (CNS), at defining the mechanisms by which CNS nAChR activity is modulated, and at determining the ion permeability of CNS nAChR channels. Our findings can be summarized as follows: (1) hippocampal neurons express at least three subtypes of CNS nAChRs--an alpha 7-subunit-bearing nAChR that subserves fast-inactivating, alpha-BGT-sensitive currents, which are referred to as type IA, and alpha 4 beta 2 nAChR that subserves slowly inactivating, dihydro-beta-erythroidine-sensitive currents, which are referred to as type II, and an alpha 3 beta 4 nAChR that subserves slowly inactivating, mecamylamine-sensitive currents, which are referred to as type III; (2) nicotinic agonists can activate a single type of nicotinic current in olfactory bulb neurons, that is, type IA currents; (3) alpha 7-subunit-bearing nAChR channels in the hippocampus have a brief lifetime, a high conductance, and a high Ca2+ permeability; (4) the peak amplitude of type IA currents tends to rundown with time, and this rundown can be prevented by the presence of ATP-regenerating compounds (particularly phosphocreatine) in the internal solution; (5) rectification of type IA currents is dependent on the presence of Mg2+ in the internal solution; and (6) there is an ACh-insensitive site on neuronal and nonneuronal nAChRs through which the receptor channel can be activated. These findings lay the groundwork for a better understanding of the physiological role of these receptors in synaptic transmission in the CNS.
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PMID:Nicotinic receptor function in the mammalian central nervous system. 761 5

It has been reported clinically that edrophonium (EDR) has a more potent antagonistic effect on the fade of twitch tension and a less potent antagonistic effect on the depressed single twitch force induced by muscle relaxants than does neostigmine (NST). However, the details of the mechanism have not yet been clarified. In this experiment, to compare the antagonistic effect of EDR and NST on the neuromuscular blocking effect of dTc, the recovery from dTc induced neuromuscular blocking effect on both the postjunctional membrane and the motor nerve terminal with EDR or NST was studied using intracellular recording techniques in rat phrenic nerve-hemidiaphragm preparations. The preparation was constantly perfused with physiological saline solution at room temperature. To determine the ACh sensitivity of the postjunctional membrane, ACh potentials were elicited and recorded. To determine the quantum release of ACh from the motor nerve terminal and its rundown, endplate potentials (EPPs) were elicited at 2Hz and recorded. ACh sensitivity was increased with EDR and NST in a dose dependent manner. The extent of increased ACh sensitivity with EDR 10(-6)M was almost equal to that with NST 10(-7)M. In this experiment, these concentrations were used to compare the antagonistic effect of EDR and NST on the effect of dTc 10(-6)M. The depressed ACh sensitivity with dTc was reversed with EDR and NST. The extent of restoration with NST was about three times that with EDR. The quantum release of ACh was increased and rundown was depressed with EDR, but NST had no effect. After pretreatment with dTc, neither EDR nor NST increased the decreased quantum release of ACh nor reversed the enhanced rundown induced by dTc. But under the same condition, both EDR and NST reversed the ACh sensitivity depressed with dTc. These results demonstrate that neither EDR nor NST were able to affect the decreased quantum release of ACh nor the enhanced rundown induced by dTc. The results also suggest that the reversal of fade of twitch tension with EDR and NST does not always result from recovery of rundown of EPP amplitude.
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PMID:[A microelectrode study of the antagonism of d-tubocurarine induced neuromuscular blockade by edrophonium and neostigmine]. 843 89

The cloning and expression of genes encoding for the human neuronal nicotinic acetylcholine receptors (nAChRs) has opened new possibilities for investigating their physiological and pharmacological properties. Cells (HEK 293) stably transfected with two of the major brain subunits, alpha4 and beta2, were characterized electrophysiologically using the patch-clamp technique. Fast application of the natural ligand ACh can evoke currents up to 3500 pA, with an apparent affinity (EC50) of 3 microM and a Hill coefficient of 1.2. The rank order of potency of four nAChR ligands to activate human alpha4beta2 receptors is (-)-nicotine > ACh > (-)-cytisine > ABT-418. At saturating concentrations, the efficacy of these ligands is ABT-418 >> (-)-nicotine > ACh >> (-)-cytisine > GTS-21 (previously named DMXB). Coapplication of 1 microM ACh with known nAChR inhibitors such as dihydro-beta-erythroidine and methyllycaconitine reversibly reduces the current evoked by the agonist with respective IC50 values of 80 nM and 1.5 microM. The current-voltage relationship of human alpha4beta2 displays a strong rectification at positive potentials. Experiments of ionic substitutions suggest that human alpha4beta2 nAChRs are permeable to sodium and potassium ions. In the "outside-out" configuration, ACh evokes unitary currents (main conductance 46 pS) characterized by a very fast rundown. Potentiation of the ACh-evoked currents is observed when the extracellular calcium concentration is increased from 0.2 to 2 mM. In contrast, however, a reduction of the evoked currents is observed when calcium concentration is elevated above 2 mM.
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PMID:Human alpha4beta2 neuronal nicotinic acetylcholine receptor in HEK 293 cells: A patch-clamp study. 898 16

1. The role of cyclic ADP ribose and ryanodine receptors in the inhibition of the M-like current (IK(M,ng)) by acetylcholine was investigated in m1 muscarinic receptor-transformed mouse neuroblastoma-rat glioma hybrid (NG108-15) cells using patch-clamp techniques and calcium microfluorimetry. 2. Acetylcholine (1-100 microM) decreased IK(M,ng) by up to 55 %. Application, via the patch pipette, of the cyclic ADP ribose antagonists 8-amino-cyclic ADP ribose (10-100 microM) and 8-bromo-cyclic ADP ribose (100-1000 microM) reduced this inhibition of IK(M,ng) in a concentration-dependent manner. The half-maximal inhibition concentrations for 8-amino- cyclic ADP ribose and 8-bromo-cyclic ADP ribose were around 40 microM and 1 mM, respectively. 3. Neither of the cyclic ADP ribose antagonists altered the amplitude of IK(M,ng) per se, or the incidence of the concurrent Ca2+-activated K+ current (IIK(Ca)) activation, also mediated by acetylcholine. 4. The ryanodine receptor modulators ryanodine (1-10 microM) and Ruthenium Red (10 microM) did not alter IK(M,ng) amplitude or IK(M,ng) inhibition mediated by acetylcholine. There was a statistically significant increase in the proportion of cells showing outward currents in the presence of Ruthenium Red. 5. Intracellular calcium levels measured with fura-2 microfluorimetry were increased with low concentrations of ryanodine (1 microM), more consistently with caffeine (10 mM), and in almost every case with both bradykinin (300 nM) and acetylcholine (100 microM). Caffeine-, but not bradykinin-evoked responses were abolished by preincubation with ryanodine (10 microM). 6. The fast 'rundown rate' of the M-current recorded in rat superior cervical ganglion cells under whole-cell conditions precluded an investigation of the effects of intracellular dialysis of cyclic ADP ribose. However, when cyclic ADP ribose (5 microM) was applied directly to the cytoplasmic face of inside-out membrane patches excised from rat superior cervical ganglion cells containing M-channels, it had no effect on the main parameters of single channel activity (conductance, mean open time or frequency of opening). 7. These results indicate that cyclic ADP ribose acts on a specific intracellular site to mediate IK(M,ng) inhibition. However, unlike previously established effects of cyclic ADP ribose, the ryanodine receptor is not required, suggesting that another molecular target may be involved. Studies at the single channel level indicate that cyclic ADP ribose may not act directly on the M-channels in inside-out patches.
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PMID:The role of ryanodine receptors in the cyclic ADP ribose modulation of the M-like current in rodent m1 muscarinic receptor-transformed NG108-15 cells. 1043 36

The "M-like" current in NG108-15 cells has two components carried by different K+ channels: a fast-deactivating component, analogous to IK(M) in sympathetic neurones and carried by KCNQ2/3 channels, and a more slowly deactivating component carried by murine erg1 (merg1) channels. The former is selectively blocked by linopirdine (< or =10 microM), the latter by WAY123,398 (< or =10 microM). Bradykinin (100 nM) inhibited 76% of the KCNQ component of current compared with 12% of the merg component. Cyclic ADP ribose (cADPR, 2 microM), introduced via the patch pipette, caused a rundown of both current components. Acetylcholine (100 microM) inhibited 89% of the KCNQ component of current compared to 34% of the merg component. After 15 min of intracellular dialysis with the cADPR antagonist 8-amino-cADP ribose (100 microM), the inhibition reduced to 40% and 19% and after 30 min it was further reduced to 8% and 5% for the KCNQ currents and merg currents respectively. These data show that both KCNQ and merg currents in NG108-15 cells can be modulated by either bradykinin or M1 muscarinic receptors. The inhibition of the KCNQ current component is more pronounced than that of the merg component. These results suggest that cADPR might be involved in M1-muscarinic inhibition of both KCNQ2/3 and merg1 channels.
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PMID:Both linopirdine- and WAY123,398-sensitive components of I K(M,ng) are modulated by cyclic ADP ribose in NG108-15 cells. 1121 Nov 7

Stimulation of muscarinic acetylcholine receptors (mAChRs) can activate an inward rectifier K(+) current (I(KACh)), which is mediated by the M(2) subtype of mAChR in cardiac myocytes. Recently, a novel delayed rectifier-like K(+) current mediated by activation of the cardiac M(3) receptors (designated I(KM3)) was identified, which is distinct from I(KACh) and other known K(+) currents. While I(KACh) is known to be a G(i) protein-gated K(+) channel, the signal transduction mechanisms for I(KM3) activation remained unexplored. We studied I(KM3) with whole-cell patch clamp and macropatch clamp techniques. Whole cell I(KM3) activated by choline persisted with minimal rundown over 2 h in presence of internal GTP. When GTP was replaced by guanyl-5'-yl thiophosphate, I(KM3) demonstrated rapid and extensive rundown. While I(KACh) (induced by ACh) was markedly reduced in cells pretreated with pertussis toxin, I(KM3) was unaltered. Intracellular application of antibodies targeting alpha-subunit of G(i/o) protein suppressed I(KACh) without affecting I(KM3). Antibodies targeting the N and the C terminus, respectively, of G(q) protein alpha-subunit substantially depressed I(KM3) but failed to alter I(KACh). The antibody against beta-subunits of G proteins inhibited both I(KACh) and I(KM3). I(KM3) activated by choline in the cell-attached mode of macropatches persisted in the cell-free configuration. Application of purified G(q) protein alpha-subunit or betagamma-subunit of G proteins or guanosine 5'-O-(thiotriphosphate) to the internal solution activated I(KM3)-like currents in inside-out patches. Our findings revealed a novel aspect of receptor-channel signal transduction mechanisms, and I(KM3) represents the first G(q) protein-coupled K(+) channel. We propose that the G protein-coupled K(+) channel family could be divided into two subfamilies: G(i) protein-coupled K(+) channel subfamily and G(q) protein-coupled K(+) channel subfamily.
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PMID:The M3 receptor-mediated K(+) current (IKM3), a G(q) protein-coupled K(+) channel. 1514 Aug 74

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