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PubMed1997

Beta-adrenoceptor-coupled Gs protein facilitates the activation of cAMP-dependent cardiac Cl- current.

Here a comparison is made between adenosine 3',5'-cyclic monophosphate (cAMP)-activated Cl- current (ICl) density and activation time course in response to beta-adrenoceptor stimulation with isoproterenol and adenylyl cyclase activation with forskolin. Saturating concentrations of isoproterenol and forskolin failed to activate an ICl in guinea pig atrial as well as in rat and frog ventricular cardiomyocytes. In guinea pig ventricular cardiomyocytes, step application of 1 microM isoproterenol induced an ICl of -0.89 +/- 0.32 pA/pF (holding potential -40 mV, temperature 22 +/- 1 degrees C). ICl activation started after 3 +/- 1 s, was complete within 44 +/- 9 s, and was abolished after cell dialysis with the Rp diastereomer of adenosine 3',5'-cyclic monophosphothioate. Stimulation with increasing concentrations of forskolin (0.01-10 microM) increased ICl density and accelerated ICl activation. With 1 microM forskolin, ICl density was maximal (-0.57 +/- 0.30 pA/pF) but significantly smaller than that achieved with 1 microM isoproterenol. Although ICl density could not be further augmented by forskolin > 1 microM, current activation (latency 28 +/- 8 s, full activation after 112 +/- 8 s with 1 microM forskolin) was further accelerated by 3 and 10 microM forskolin. However, ICl activation with 10 microM forskolin was still slower than that with 1 microM isoproterenol. A low isoproterenol concentration (1 nM), which did not activate ICl by itself, accelerated the 1 microM forskolin-induced activation of ICl by 35%; this speeding up was abolished after cell dialysis with guanosine 5'-O-(2-thiodiphosphate). ICl deactivation after the washout of 1 microM forskolin or 1 microM isoproterenol followed a similar time course. After stimulation with 10 microM forskolin or 1 microM forskolin + 1 microM isoproterenol, but not with 1 microM forskolin + 1 nM isoproterenol, the decay of ICl was significantly delayed. These results indicate that both cAMP-dependent and cAMP-independent G protein pathways contribute to the regulation of guinea pig ventricular ICl.

Adrenergic beta-Agonists↗
PubMed2003

Chloride influx aggravates Ca2+-dependent AMPA receptor-mediated motoneuron death.

AMPA receptor-mediated excitotoxicity has been implicated in the pathogenesis of stroke, neurotrauma, epilepsy, and many neurodegenerative diseases such as motoneuron disease. We studied the role of Cl- in AMPA receptor-mediated Ca2+-dependent excitotoxicity in cultured rat spinal motoneurons. Using the gramicidin perforated patch-clamp technique, the intracellular Cl- concentration could be calculated from the reversal potential of the GABA-induced current. The membrane depolarization caused by AMPA receptor stimulation resulted in Cl- influx through 5-nitro-2(3-phenylpropyl-amino) benzoic acid- and niflumic acid-sensitive Cl- channels. Cl- influx during AMPA receptor stimulation aggravated excitotoxic motoneuron death by two mechanisms: an increase of AMPA receptor conductance and an elevation of the Ca2+ driving force through a partial repolarization. The Cl- influx during AMPA receptor stimulation was enhanced by coadministration of GABA. This resulted in an increased Ca2+ influx and an enhanced cell death, suggesting that concomitant GABAergic stimulation may aggravate excitotoxic motoneuron death.

Animals↗
PubMed2004

Calcium handling in afferent arterioles.

The cytosolic intracellular calcium concentration ([Ca(2+)](i)) is a major determining factor in the vascular smooth muscle tone. In the afferent arteriole it has been shown that agonists utilizing G-protein coupled receptors recruit Ca(2+) via release from intracellular stores and entry via pathways in the plasma membrane. The relative importances of entry vs. mobilization seem to differ between different agonists, species and preparations. The entry pathway might include different types of voltage sensitive Ca(2+) channels located in the plasmalemma such as dihydropyridine sensitive L-type channels, T-type channels and P/Q channels. A role for non-voltage sensitive entry pathways has also been suggested. The importance of voltage sensitive Ca(2+) channels in the control of the tone of the afferent arteriole (and thus in the control of renal function and whole body control of extracellular fluid volume and blood pressure) sheds light on the control of the membrane potential of afferent arteriolar smooth muscle cells. Thus, K(+) and Cl(-) channels are of importance in their role as major determinants of membrane potential. Some studies suggest a role for calcium-activated chloride (Cl(Ca)) channels in the renal vasoconstriction elicited by agonists. Other investigators have found evidence for several types of K(+) channels in the regulation of the afferent arteriolar tone. The available literature in this field regarding afferent arterioles is, however, relatively sparse and not conclusive. This review is an attempt to summarize the results obtained by others and ourselves in the field of agonist induced afferent arteriolar Ca(2+) recruitment, with special emphasis on the control of voltage sensitive Ca(2+) entry. Outline of the Manuscript: This manuscript is structured as follows: it begins with an introduction where the general role for [Ca(2+)](i) as a key factor in the regulation of the tone of vascular smooth muscles (VSMC) is detailed. In this section there is an emphasis is on observations that could be attributed to afferent arteriolar function. We then investigate the literature and describe our results regarding the relative roles for Ca(2+) entry and intracellular release in afferent arterioles in response to vasoactive agents, with the focus on noradrenalin (NA) and angiotensin II (Ang II). Finally, we examine the role of ion channels (i.e. K(+) and Cl(-) channels) for the membrane potential, and thus activation of voltage sensitive Ca(2+) channels.

Animals↗
PubMed1995

NMDA receptors in rat cerebellum and forebrain: subtle differences in pharmacology and modulation.

Binding of [3H]glutamate, [3H]glycine, and the glutamate antagonist [3H]CGS-19755 to NMDA-type glutamate receptors was examined in homogenates of rat forebrain and cerebellum. Most glutamate agonists had a higher affinity at the [3H]glutamate binding site of cerebellar NMDA receptors as compared with forebrain, whereas all the glutamate antagonists examined showed the reverse relationship. The [3H]glycine binding site of forebrain and cerebellar NMDA receptors showed a similar pharmacology in both brain regions. In the cerebellum, however, [3H]glycine bound to a second site with a 10-fold lower affinity and with a pharmacology that resembled that of the glycine/strychnine chloride channel. [3H]-Glutamate binding was not affected by glycine agonists or antagonists, nor was [3H]glycine binding affected by glutamate agonists in either forebrain or cerebellum. Both CGS-19755 and 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid, glutamate antagonists, reduced [3H]-glycine binding in cerebellum, whereas only CGS-19755 was effective in forebrain. Glycine agonists and antagonists modulated [3H]CGS-19755 binding in forebrain and cerebellum to different extents in the two brain regions. From these studies we conclude that the cerebellar NMDA receptor has a different pattern of modulation at glutamate and glycine sites and that glycine may play a more important role in the control of NMDA function in the cerebellum as compared with forebrain.

Animals↗
PubMed2003

Pharmacological discrimination between muscarinic receptor signal transduction cascades with bethanechol chloride.

1. Muscarinic agonist specificity is limited, making it difficult to match receptor subtypes with signal transduction cascades that mediate ion channel modulation. We have characterized the inhibitory effects of two muscarinic agonists, oxotremorine-M (Oxo-M) and bethanechol chloride (BeCh), on Ca(2+) currents in neonatal rat superior cervical ganglion neurons. 2. Oxo-M-mediated (10 micro M) inhibition occurred via two signaling pathways. The first pathway inhibited whole cell peak currents, consisting primarily of N-type current, but not FPL 64176-induced, long-lasting tail currents, comprised entirely of L-type current. Inhibited currents displayed slowed activation kinetics and voltage dependence, characteristics of membrane-delimited inhibition. Current inhibition was blocked by the selective M(2) receptor antagonist, methoctramine (METH; 100 nM), or following pertussis toxin (PTX) pretreatment. 3. Activation of the second pathway inhibited both peak and long-lasting tail currents. This pathway was voltage-independent, PTX-insensitive, but sensitive to internal Ca(2+) chelator concentration. Muscarinic toxin 7 (MT-7, 100 nM), an irreversible M(1) receptor antagonist, eliminated this inhibition. Oxo-M (100 micro M) decreased L- and N-type channel activities in cell-attached patches, indicating that a diffusible second messenger is involved. 4. BeCh (100 micro M) also inhibited whole cell currents via the membrane-delimited pathway. Blocking M(4) receptors with 100 nM pirenzepine (in the presence of MT-7) had no effect, while antagonizing M(2) receptors with METH abolished inhibition. Concentrations of BeCh as high as 3 mM failed to inhibit either peak or long-lasting tail currents following PTX pretreatment. 5. These results indicate that BeCh may be an effective tool for selectively activating M(2) receptor stimulation of the membrane-delimited pathway.

Animals↗
PubMed1997

Role of calcium-activated chloride current in regulating pulmonary vasomotor tone.

Many agonists induce vasoconstriction by releasing intracellularly stored Ca2+ and promoting Ca2+ influx. Activation of Ca(2+)-activated Cl- (ClCa) channels may be a critical mechanism by which a rise in intracellular free Ca2+ concentration ([Ca2+]i) causes membrane depolarization that serves to sustain the elevated [Ca2+]i and maintain vascular tone. In this study the biophysical and pharmacological properties of ClCa currents [ICKCa] were characterized in rat pulmonary artery (PA) smooth muscle cells, and their relationship to the regulation of pulmonary vascular tone was determined. When K+ currents were eliminated by using Cs(+)-containing internal solution, depolarization elicited an inward Ca2+ current followed by a time-dependent outward Cl- current that reversed near Cl- equilibrium potential. Repolarizing voltage steps produced a large inward tail Cl- current that also reversed at a potential close to Cl- equilibrium potential. Replacement of extracellular Ca2+ with Ba2+ significantly augmented the Ca2+ current but abolished the Cl- currents. The Cl- channel blocker niflumic acid (10-50 microM) diminished the time-dependent outward Cl- current and the inward tail Cl- current, decreased serotonin-induced membrane depolarization, and inhibited agonist-induced PA contraction. In the absence of extracellular Ca2+, cyclopiazonic acid, which releases Ca2+ from sarcoplasmic reticulum, elicited an inward Cl- current at a holding potential of -70 mV. These results indicate that rat PA myocytes possess ClCa channels that are activated by depolarization-induced Ca2+ influx and agonist-induced Ca2+ release. This Cl- current contributes to agonist-induced pulmonary vasoconstriction via membrane depolarization.

Animals↗
PubMed2001

Chlorzoxazone or 1-EBIO increases Na(+) absorption across cystic fibrosis airway epithelial cells.

Previous studies demonstrated that chlorzoxazone or 1-ethyl-2-benzimidazolinone (1-EBIO) enhances transepithelial Cl(-) secretion by increasing basolateral K(+) conductance (G(K)) (Singh AK, Devor DC, Gerlach AC, Gondor M, Pilewski JM, and Bridges RJ. J Pharmacol Exp Ther 292: 778-787, 2000). Hence these compounds may be useful to treat cystic fibrosis (CF) airway disease. The goal of the present study was to determine whether chlorzoxazone or 1-EBIO altered ion transport across Delta F508-CF transmembrane conductance regulator homozygous CFT1 airway cells. CFT1 monolayers exhibited a basal short-circuit current that was abolished by apical amiloride (inhibition constant 320 nM) as expected for Na(+) absorption. The addition of chlorzoxazone (400 microM) or 1-EBIO (2 mM) increased the amiloride-sensitive I(sc) approximately 2.5-fold. This overlapping specificity may preclude use of these compounds as CF therapeutics. Assaying for changes in the basolateral G(K) with a K(+) gradient plus the pore-forming antibiotic amphotericin B revealed that chlorzoxazone or 1-EBIO evoked an approximately 10-fold increase in clotrimazole-sensitive G(K). In contrast, chlorzoxazone did not alter epithelial Na(+) channel-mediated currents across basolateral-permeabilized monolayers or in Xenopus oocytes. These data further suggest that alterations in basolateral G(K) alone can modulate epithelial Na(+) transport.

Amiloride↗
PubMed1992

Barbiturate tolerance: effects on GABA-operated chloride channel function.

Male ICR mice were fed powdered laboratory chow containing phenobarbital for 7 days to induce tolerance. Mice were sacrificed and brains assayed for changes in GABA-mediated chloride flux into brain membrane vesicles (microsacs). Concentration-dependent stimulation of chloride flux by GABA alone was not affected by the development of tolerance to phenobarbital. Phenobarbital potentiation of GABA-mediated chloride flux was significantly attenuated in the membranes prepared from phenobarbital-tolerant mice compared with those from pair-fed control mice. Similarly, stimulation of GABA-mediated flux by the benzodiazepine, flunitrazepam was also depressed in membranes from tolerant mice. However, the ability of ethanol and the benzodiazepine inverse agonist FG-7142 to modulate GABA-gated chloride flux was not affected by the development of phenobarbital tolerance. No significant changes in saturation [3H]diazepam binding parameters were observed. These findings suggest that there is a degree of cross-tolerance between phenobarbital and benzodiazepine agonist at the level of the GABA-operated chloride channel. Furthermore, although some reports have demonstrated behavioral cross-tolerance between ethanol and barbiturates, the present data suggest different mechanisms of tolerance development for these intoxicants at the level of the GABAA receptor chloride channel complex.

Animals↗
PubMed1998

Developmental changes of GABA(A) receptor-chloride channels in rat Meynert neurons.

The developmental changes of GABA(A) receptors were investigated in Meynert neurons freshly dissociated from day 0, 2 week-, and 6 month-old rats using both nystatin and gramicidin perforated patch recording modes under voltage-clamp conditions. The age-related changes in the current amplitude and threshold concentration in the concentration-response relationships for GABA indicated the developmental alteration of the GABA(A) receptor subunits and the channel density. The GABA-induced E(Cl-) measured by the gramicidin perforated patch mode shifted to more negative with development. The decay time constant of GABAergic inhibitory postsynaptic spontaneous currents (sIPSCs) in the synaptic active zone accelerated with aging. The GABA-induced currents were potentiated in a concentration dependent manner in the presence of benzodiazepine (BZP) agonists, diazepam (DZP) and zolpidem (ZPM). The potentiation rate of DZP on the GABA(A) response decreased with aging, but not in the case of ZPM, which demonstrated a stronger action in the aging rat neurons. These results suggested that the GABA(A) receptor x Cl- channel complexes may thus change both the assembly and interaction of subunits as well as their functional roles with aging.

Animals↗
PubMed1994

Regulation of cyclic AMP-dependent Cl- channel in heart.

(1) alpha 1-Adrenoceptor stimulation inhibited the beta-adrenergic activation of Cl- current in guinea-pig ventricular cells. This alpha 1- and beta-adrenergic interaction appeared to be upstream in the cascade of adenylate cyclase activation. (2) Single Cl(-)-channel currents were recorded in cell-attached and excised outside-out patch membranes. Experiments were performed to investigate the dependence of channel behavior on the agonist concentrations.

Adrenergic alpha-Agonists↗
PubMed1990

Simultaneous analysis of cell Ca2+ and Ca2(+)-stimulated chloride conductance in colonic epithelial cells (HT-29).

We used perforated patch, whole-cell current recordings and video-based fluorescence ratio imaging to monitor the relation of plasma membrane ionic conductances to intracellular free Ca2+ within individual colonic epithelial cells (HT-29). The Ca2(+)-mediated agonist, neurotensin, activated K+ and Cl- conductances that showed different sensitivities to [Ca2+]i. The Cl- conductance was sensitive to increases or decreases in [Ca2+]i around the resting value of 76 +/- 32 (mean +/- SD) nM (n = 46), whereas activation of the K+ conductance required at least a 10-fold rise in [Ca2+]i. Neurotensin increased [Ca2+]i by stimulating a transient intracellular Ca2+ release, which was followed by a sustained rise in [Ca2+]i due to Ca2+ influx from the bath. The onset of the initial [Ca2+]i transient, monitored at a measurement window over the cell interior, lagged behind the rise in Cl- current during agonist stimulation. This lag was not present when the [Ca2+]i rise was due to Ca2+ entry from the bath, induced either by the agonist or by the Ca2+ ionophore ionomycin. The temporal differences in [Ca2+]i and Cl- current during the agonist-induced [Ca2+]i transient can be explained by a localized Ca2+ release from intracellular stores in the vicinity of the plasma membrane Cl- channel. Chloride currents recover toward basal values more rapidly than [Ca2+]i after the agonist-induced [Ca2+]i transient, and, during a sustained neurotensin-induced [Ca2+]i rise, Cl- currents inactivate. These findings suggest that an inhibitory pathway limits the increase in Cl- conductance that can be evoked by agonist. Because this Cl- current inhibition is not observed during a sustained [Ca2+]i rise induced by ionomycin, the inhibitory pathway may be mediated by another agonist-induced messenger, such as diacylglycerol.

Calcium↗
PubMed1991

Role of the GABA chloride ion channel component on aggressive behavior in the male crab.

Picrotoxin blocking effects on GABA-induced inhibition of lateral merus display in the male crab Carcinus mediterraneus suggest that the chloride ion channel component of the GABA molecule is involved in the control of this defensive behavior. The low GABA doses (3 and 5 micrograms/g body weight) inhibited lateral merus display as early as 10 min after drug treatment while the administration of higher GABA concentrations (greater than 5 micrograms/g) prolonged the duration of the behavioral effects. The administration of 1 microgram/g picrotoxin to the animals treated with the effective GABA doses (5, 10 and 20 micrograms/g) restored lateral merus display. The antagonizing activity of picrotoxin on the inhibitory GABA effects, in a temporal manner, demonstrates that GABAergic sites other than peripheral ones are probably participating with the regulation of this agonistic posture. Quantitative autoradiography results revealed interesting receptor levels changes of the specific chloride ion channel antagonist [35S] t-butylbicyclophosphorothionate in the different brain areas of the male crab displaying lateral merus with respect to normal nonreactive animals. Elevated receptor binding levels were encountered in the middle and posterior brain area whereas low levels were obtained at the anterior level. Both the behavioral and autoradiographic results suggest that the defensive type of aggression behavior in crustacean may not only be mediated by a peripherally controlled GABA-gated chloride ion flux but also by a central GABAergic mechanism.

Aggression↗
PubMed2006

An activity-dependent increased role for L-type calcium channels in exocytosis is regulated by adrenergic signaling in chromaffin cells.

Chromaffin cells of the adrenal medulla represent a primary output of the sympathetic nervous system. Their electrical stimulation evokes the fusion of large dense core granules with the cell membrane and the exocytic release of multiple transmitter molecules into the circulation. There the transmitters contribute to the regulation of basic metabolism of the organism. Under physiological activity, granule fusion and transmitter release are limited by activity-dependent Ca(2+) influx, entering through multiple isoforms of voltage-gated calcium channels. In this study we utilize perforated-patch voltage-clamp recordings and depolarize mouse chromaffin cells in situ with action potential-like waveforms to mimic physiological firing. We measure calcium influx through specific isoforms and measure cell capacitance as an index of granule fusion. Combining these approaches we calculate specific stimulus-secretion efficiencies for L-type, N-type, P/Q-type and R-type calcium channels under varied physiological activity levels. Current influx through all channel subtypes exhibited an activity-dependent depression. As expected P/Q-type channels, while responsible for modest Ca(2+) influx, are tightly coupled to catecholamine secretion under all conditions. We further find that stimulation designed to match sympathetic input under the acute stress response recruits L-type channels to a state of enhanced stimulus-secretion efficiency. N- and R-type channels do not undergo activity-dependent recruitment and remain loosely coupled to the secretion. Thus, only L-type channels exhibit activity-dependent changes in their stimulus-secretion function under physiological stimulation. Lastly, we show that treatment with the beta-adrenergic agonist, isoproterenol, specifically blocks the increase in the stimulus-secretion function of L-type channels. Thus, increased cell firing specifically enhances stimulus-secretion coupling of L-type Ca(2+) channels in chromaffin cells in situ. This mechanism is regulated by an adrenergic signaling pathway.

Action Potentials↗
PubMed1994

[D-Pen2-D-Pen5]enkephalin, a delta opioid agonist, given intracerebroventricularly in the mouse produces antinociception through medication of spinal GABA receptors.

Intracerebroventricular (ICV) administration of [D-Pen2-D-Pen5]enkephalin (DPDPE), a delta opioid receptor agonist, activates a descending antinociceptive pathway that inhibits the tail-flick response in mice. Involvement of spinal GABA receptors in this response was studied by giving GABA antagonist intrathecally. First, antinociception produced by intrathecally administered isoguvacine, a GABAA agonist, was inhibited by intrathecal bicuculline (GABA receptor antagonist) or picrotoxin (chloride channel antagonist). Then, antinociception induced by ICV DPDPE was antagonized by intrathecal picrotoxin and bicuculline in a dose-and time-dependent manner. Second, intrathecal administration of 2-hydroxysaclofen, a GABAB antagonist (which inhibited antinociception induced by a GABAB agonist, baclofen, given IT), produced a shift of the dose-response curve for ICV DPDPE to the right. GABAA agonist, baclofen, given IT), produced a shift of the dose-response curve for ICV DPDPE to the right. GABAA and B antagonists given together intrathecally produced a greater than additive antagonistic effect against ICV DPDPE-induced antinociception. Thus, the delta agonist action of DPDPE in the brain leads to activation of descending spinal pathways which involve mediation by spinal GABAA and GABAB receptors in the antinociceptive response.

Analgesics↗
PubMed1991

Role of signal transduction in anesthetic action. Alpha 2 adrenergic agonists.

The molecular mechanism for general anesthetic action is not known. The alpha 2 adrenergic agonists represent a novel class of "anesthetic-like" agent because of their selectivity for receptor binding sites and because the transmembrane signaling systems mediating their biologic responses in non-CNS systems are known. We have begun to characterize the signal transduction pathway involved in the anesthetic-like action of the alpha 2 adrenergic agonists. The alpha 2 adrenergic agonists potently decrease both central noradrenergic neurotransmission and halothane anesthetic requirements (MAC). Since MAC is only reduced by 30-40% when noradrenergic neurotransmission is totally abolished and since the reduction in MAC with the highly selective alpha 2 adrenergic agonists exceeds 90%, factors in addition to noradrenergic neurotransmission must be contributing to the anesthetic action of the alpha 2 agonists. Studies with the superselective alpha 2 agonist dexmedetomidine confirmed this, as the alpha 2 agonist could still reduce the MAC for halothane in rats depleted of their central norepinephrine stores. The profound reduction in anesthetic requirements with dexmedetomidine raised the possibility that alpha 2 adrenergic agonists may be considered an anesthetic hypnotic agent by itself. This sole anesthetic hypnotic response was established together with the confirmation that a central alpha 2 adrenoceptor mediated this action. Subsequently, data using molecular biologic techniques suggested that the alpha 2 C4 isoreceptor was the probable receptor that mediated the anesthetic response. We further explored the postreceptor effector mechanism for the signal transduction pathway for alpha 2 anesthetic action and identified the participation of two other molecular components, namely, a pertussis-toxin-sensitive G protein and a 4-aminopyridine-sensitive ion channel. Whether the signal transduction pathway for alpha 2 anesthetic action mediates the further response to other non-alpha 2 anesthetic agents needs to be defined.

Adrenergic alpha-Agonists↗
PubMed1995

Choline blocks large conductance KCa channels in mammalian sympathetic neurones.

Using the outside-out configuration of the patch clamp technique, we examined the effects of externally applied choline chloride (ChCl) on the large-conductance calcium-dependent K+ (KCa) channel in sympathetic neurones of the rabbit coeliac ganglion. Isotonically replacing the bath sodium chloride by ChCl significantly decreased the unitary current amplitude of the KCa channels but did not affect their gating properties. The blocking effect was dose-dependent and required 24 mM ChCl to reach half-reduction of the KCa channel conductance (from 134 to 64 pS). In whole-cell voltage-clamped neurones, ChCl activated both nicotinic and muscarinic receptors, which induced various membrane current changes including Ca2+ current decrease. We therefore tested the effects of the cholinergic agonists acetylcholine and carbachol on excised KCa channels. Both agents failed to mimic the blocking effects of ChCl. We therefore conclude that KCa channels in sympathetic neurones are occluded by external choline chloride.

Animals↗