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PubMed1989

Inhibition of the bovine-heart mitochondrial F1-ATPase by cationic dyes and amphipathic peptides.

The bovine heart mitochondrial F1-ATPase is inhibited by a number of amphiphilic cations. The order of effectiveness of non-peptidyl inhibitors examined as assessed by the concentration estimated to produce 50% inhibition (I0.5) of the enzyme at pH 8.0 is: dequalinium (8 microM), rhodamine 6G (10 microM), malachite green (14 microM), rosaniline (15 microM) greater than acridine orange (180 microM) greater than rhodamine 123 (270 microM) greater than rhodamine B (475 microM), coriphosphine (480 microM) greater than safranin O (1140 microM) greater than pyronin Y (1650 microM) greater than Nile blue A (greater than 2000 microM). The ATPase activity was also inhibited by the following cationic, amphiphilic peptides: the bee venom peptide, melittin; a synthetic peptide corresponding to the presence of yeast cytochrome oxidase subunit IV (WT), and amphiphilic, synthetic peptides which have been shown (Roise, D., Franziska, T., Horvath, S.J., Tomich, J.M., Richards, J.H., Allison, D.S. and Schatz, G. (1988) EMBO J. 7, 649-653) to function in mitochondrial import when attached to dihydrofolate reductase (delta 11.12, Syn-A2, and Syn-C). The order of effectiveness of the peptide inhibitors as assessed by I0.5 values is: Syn-A2 (40 nM), Syn-C (54 nM) greater than melittin (5 microM) greater than WT (16 microM) greater than delta 11,12 (29 microM). Rhodamines B and 123, dequalinium, melittin, and Syn-A2 showed noncompetitive inhibition, whereas each of the other inhibitors examined (rhodamine 6G, rosaniline, malachite green, coriphosphine, acridine orange, and-Syn-C) showed mixed inhibition. Replots of slopes and intercepts from Lineweaver-Burk plots obtained for dequalinium were hyperbolic indicating partial inhibition. With the exception of Syn-C, for which the slope replot was hyperbolic and the intercept replot was parabolic, steady-state kinetic analyses indicated that inhibition by the other inhibitors was complete. The inhibition constants obtained by steady-state kinetic analyses were in agreement with the I0.5 values estimated for each inhibitor examined. Rhodamine 6G, rosaniline, dequalinium, melittin, Syn-A2, and Syn-C were observed to protect F1 against inactivation by the aziridinium of quinacrine mustard in accord with their experimentally determined I0.5 values.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1987

[An evaluation of the antibacterial effectiveness of bisdequalinium acetate and sodium hypochlorite].

The antimicrobial effectiveness of sodium hypochlorite and bis-dequalinium acetate was evaluated in vitro using three different microorganisms. The solutions were prepared in various concentrations and microorganisms were exposed to these solutions for 5, 10, 15 min. then placed into a culture medium, incubated and determined the presence or absence of growth. These results were compared with those obtained with phenol. The following conclusions were drawn from this study: 1. Of the solutions tested Bis-dequalinium acetate was the most effective antimicrobial agent. And 1.25/1000 Bis-dequalinium acetate is appropriate for the clinical use. 2. Sodium Hypochlorite is the least effective compared with Bis-dequalinium acetate and phenol. 2/100 NaOCl is agreeable for the clinical use. 3. Normal saline exhibits no antimicrobial properties.

Bacillus subtilis↗
PubMed1998

Determination of antibacterial quaternary ammonium compounds in lozenges by capillary electrophoresis.

A method for the specific determination of three quaternary ammonium compounds, benzalkonium chloride, cetylpyridinium chloride and dequalinium chloride, used as antibacterial agents in candy-based lozenges, is described based on capillary zone electrophoresis. It is shown that, following optimisation of buffer composition with respect to organic modifier concentration. pH and buffer concentration together with the inclusion of sodium dodecylsulphate as an ion-pairing agent in the case of dequalinium chloride, these analytes migrate in less than 5 min. The resultant electrophoretic peaks are sharp and readily quantified. The individual alkyl components of benzalkonium chloride can be resolved as can related impurities in dequalinium chloride lozenges. The quantitative characteristics of the assay method, based on peak areas normalised with respect to migration times, are reported and the method is compared with a previously published method based on liquid chromatography.

Anti-Infective Agents↗
PubMedDate not supplied

Selective DNA release from DQAsome/DNA complexes at mitochondria-like membranes.

The number of diseases found to be associated with defects of the mitochondrial genome has grown significantly over the past decade (Wallace 1999). Despite major advances in understanding mtDNA defects at the genetic and biochemical level, there is no satisfactory treatment available for the vast majority of patients and the exploration of gene therapeutic approaches is highly warranted. However, mitochondrial gene therapy still appears only theoretical and speculative. Any possibility for gene replacement depends on the use of a yet unavailable mitochondria-specific transfection vector. Mitochondria-specific vectors must posses two properties: they have to transport DNA to the side of mitochondria; they must not release DNA during endocytosis. Amphiphile compounds with delocalized cationic charge centers such as rhodamine 123 and the bolaamphiphile dequalinium have long been known to accumulate in mitochondria. Sufficient lipophilicity combined with delocalization of the positive charge to reduce the free energy change when moving from an aqueous to a hydrophobic environment are believed to be prerequisite for mitochondrial accumulation in response to the mitochondrial membrane potential. We have recently succeeded in preparing cationic vesicles made of dequalinium that we termed DQAsomes (Weissig et al. 1998a). We have shown that DQAsomes bind and protect DNA against DNase activity (Lasch et al. 1999). Based on the intrinsic property of dequalinium to preferentially accumulate in mitochondria in response to the electrochemical gradient at the mitochondrial membrane, we believe that DQAsomes can serve as a vector to deliver DNA to mitochondria in living cells. As a first step in the development of mitochondria-specific DNA delivery systems, we report here that DQAsome/DNA complexes selectively release DNA at cardiolipin-rich liposomes mimicking both the inner and the outer mitochondrial membrane. We demonstrate that DNA remains tightly associated with DQAsomes in the presence of an excess of anionic lipids other than cardiolipin.

Cardiolipins↗
PubMed2000

Mitochondriotropic cationic vesicles: a strategy towards mitochondrial gene therapy.

The number of diseases found to be associated with defects of the mitochondrial genome has grown significantly over the last decade. Despite major advances in understanding mtDNA defects at the genetic and biochemical level, there is no satisfactory treatment for the vast majority of patients available. This is largely due to the fact that almost all mitochondrial DNA defects involve the final common pathway of oxidative metabolism making it impossible to bypass the defect by giving alternative metabolic carriers of energy. These seemingly objective limitations of conventional biochemical treatment for patients with detects of mtDNA warrant the exploration of gene therapeutic approaches. However, mitochondrial gene therapy still appears only theoretical and speculative. Any possibility for gene replacement is dependent on the use of a yet unavailable mitochondria-specific transfection vector. Based upon an analysis of the self-assembly behavior of dequalinium, a cationic single-chain bolaamphiphile which is known to selectively accumulate in mitochondria, we have developed a whole new strategy for mitochondria-specific DNA delivery. We have succeeded in preparing vesicles made of dequalinium, which we termed DQAsomes (U.S. Patent 6,090,619). We have shown that DQAsomes efficiently bind and protect DNA and we could demonstrate that DQAsome/DNA complexes selectively release DNA at cardiolipin-rich liposomes mimicking both, the inner and the outer mitochondrial membrane. Based on the intrinsic property of dequalinium to preferentially accumulate in mitochondria in response to the electrochemical gradient at the mitochondrial membrane and based on the selective DNA release at mitochondria-like membranes we propose DQAsomes as the first mitochondria-specific vector to deliver DNA to mitochondria in living cells.

Animals↗
PubMed2000

The pharmacology of hSK1 Ca2+-activated K+ channels expressed in mammalian cell lines.

The pharmacology of hSK1, a small conductance calcium-activated potassium channel, was studied in mammalian cell lines (HEK293 and COS-7). In these cell types, hSK1 forms an apamin-sensitive channel with an IC(50) for apamin of 8 nM in HEK293 cells and 12 nM in COS-7 cells. The currents in HEK293 cells were also sensitive to tubocurarine (IC(50)=23 microM), dequalinium (IC(50)=0.4 microM), and the novel dequalinium analogue, UCL1848 (IC(50)=1 nM). These results are very different from the pharmacology of hSK1 channels expressed in Xenopus oocytes and suggest the properties of the channel may depend on the expression system. Our findings also raise questions about the role of SK1 channels in generating the apamin-insensitive slow afterhyperpolarization observed in central neurones.

Animals↗
PubMed1998

KATP channel blocking actions of quaternary ions play no role in their antiproliferative action on mouse leukaemia and rat vascular smooth muscle cells in vitro.

1. The aim of the present study was to investigate the possibility that, in the two cell lines examined, alterations in cell growth caused by lipophilic quaternary ions may involve KATP channels. We examined the effect of tetraphenylphosphonium (TPP), tetraphenylboron (TPB), rhodamine 123, dequalinium chloride (DECA) and the non-quaternary ion cisplatin on the proliferation of L1210 mouse leukaemia cells and rat smooth muscle cells in vitro. The KATP channel opener levcromakalim (LKM) and the KATP channel antagonist glibenclamide were also tested. 2. From growth-inhibition studies, the rank order of potency (based on pIC50 values) using L1210 leukaemia cells was: DECA (6.61) > cisplatin (6.09) = rhodamine 123 (6.01) > TPP (5.61) > TPB (4.25). Levcromakalim and glibenclamide were found to be inactive at the maximum concentrations used (100 mumol/L). A different rank order of potency was obtained in rat aortic smooth muscle cells: cisplatin (6.33) > DECA (5.67) > TPP (4.96) > rhodamine 123 (4.1). Tetraphenylboron (30 mumol/L), LKM (100 mumol/L) and glibenclamide (100 mumol/L) were found to be inactive. 3. When the negatively charged TPB (30 mumol/L) was combined with some of the active agents, the potency of the active agents was increased. Thus, in L1210 cells, rhodamine 123, DECA and TPP were all more potent at inhibiting cell growth in the presence of TPB. Tetraphenylboron had no effect on cisplatin in this cell line. In rat smooth muscle cells, TPB (30 mumol/L) potentiated the effect of rhodamine 123 but had no effect on the actions of cisplatin, DECA or TPP. 4. In functional studies, rhodamine 123 was a weak antagonist of the vasorelaxant responses to the KATP channel opener LKM in the porcine right circumflex artery in vitro. The pKB value obtained for rhodamine 123 at 100 mumol/L was 4.95. Dequalinium chloride was inactive. 5. We found no correlation between the actions of the compounds tested to antagonise KATP channels and their ability to inhibit cell proliferation. In addition, compounds known to regulate KATP channel activity failed to influence proliferative rates. These results suggest that KATP channels are not involved in the antiproliferative action of TPP and other quaternary ions in the two cell lines studied.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1980

Micellar properties and surface activity of some bolaform drugs in aqueous solution.

The micellar properties of a series of dicationic drugs with structures resembling those of the bolaform electrolytes have been examined using light scattering, surface tension and conductivity techniques. The compounds investigated included, demecarium bromide, ambenonium chloride, dequalinium acetate, distigmine bromide and chlorhexidine acetate. Demecarium and dequalinium formed micelles at critical concentrations of 9 x 10(-3) and 4 x 10(-3) mol kg-1 respectively. No significant association of chlorhexidine acetate could be detected, contrary to previous reports.

Ambenonium Chloride↗
PubMed2003

Cloning and expression of a small-conductance Ca(2+)-activated K+ channel from the mouse cochlea: coexpression with alpha9/alpha10 acetylcholine receptors.

Functional interactions between ligand-gated, voltage-, and Ca(2+)-activated ion channels are essential to the properties of excitable cells and thus to the working of the nervous system. The outer hair cells in the mammalian cochlea receive efferent inputs from the brain stem through cholinergic nerve fibers that form synapses at their base. The acetylcholine released from these efferent fibers activates fast inhibitory postsynaptic currents mediated, to some extent, by small-conductance Ca(2+)-activated K+ channels (SK) that had not been cloned. Here we report the cloning, characterization, and expression of a complete SK2 cDNA from the mouse cochlea. The cDNAs of the mouse cochlea alpha9 and alpha10 acetylcholine receptors were also obtained, sequenced, and coexpressed with the SK2 channels. Human cultured cell lines transfected with SK2 yielded Ca(2+)-sensitive K+ current that was blocked by dequalinium chloride and apamin, known blockers of SK channels. Xenopus oocytes injected with SK2 in vitro transcribed RNA, under conditions where only outward K+ currents could be recorded, expressed an outward current that was sensitive to EGTA, dequalinium chloride, and apamin. In HEK-293 cells cotransfected with cochlear SK2 plus alpha9/alpha10 receptors, acetylcholine induced an inward current followed by a robust outward current. The results indicate that SK2 and the alpha9/alpha10 acetylcholine receptors are sufficient to partly recapitulate the native hair cell efferent synaptic response.

Acetylcholine↗
PubMed1991

Enhanced in vitro uptake and retention of 3H-tetraphenylphosphonium by nervous system tumor cells.

Photodynamic therapy is a promising treatment for human brain tumors because of the selective retention of certain compounds by tumor cells. Certain lipophilic cationic compounds, such as tetraphenylphosphonium (TPP), are selectively taken up by a variety of carcinomas. Although preferential retention of TPP has been demonstrated for the breast carcinoma cell line MCF-7, this compound had not been tested previously on cells derived from nervous system tumors. In the present study, tritiated-TPP (3H-TPP) uptake and retention for eight different cell cultures of three histologically different types of nervous system tumors was measured and the data were compared to a positive control (MCF-7) and negative controls (normal African Green monkey kidney epithelium (CV-1) and the normal human fibroblast (WI-38) cell lines). Uptake and retention characteristics could be grouped by specific pathological tumor types, but individual tumor variability was notable. Malignant astrocytoma (grade III/III glioblastoma) and malignant neurofibrosarcoma cells showed preferential uptake and retention of 3H-TPP relative to meningioma cells and normal controls. A clonogenic assay utilizing the cytotoxic lipophilic cationic compound dequalinium showed strong retainers of 3H-TPP to be more susceptible to the effects of dequalinium than weak retainers. These data demonstrate that certain human and experimental animal nervous system tumor cell lines retain lipophilic compounds possessing a delocalized positive charge. Lipophilic cationic compounds may be useful in the intraoperative delineation of tumor margins and in the photodynamic therapy of certain nervous system tumors.

Animals↗
PubMedDate not supplied

Capillary electrophoresis and liquid chromatography in the analysis of some quaternary ammonium salts used in lozenges as antibacterial agents.

A comparison is made of the relative merits of high-performance liquid chromatography and capillary electrophoresis, both using direct UV detection, for the determination of three quaternary ammonium compounds used as the active antibacterial ingredient in lozenge formulations. While both techniques are capable of separating the compounds cetylpyridinium chloride, dequalinium chloride, and benzalkonium chlorides, the liquid chromatographic method involving ion pairing and using a 5-micron cyanopropyl stationary phase, was unable to resolve the benzalkonium chlorides from the lozenge excipients and quantitation was not possible. The capillary electrophoresis method using a 205-mm 50-micron-i.d. capillary with a running buffer of 50% vol/vol 50 mM phosphate buffer at pH 3 provided superior resolution of the three antibacterials in all lozenge formulations. This system was also capable of resolving impurities in the dequalinium chloride both in the standard and in lozenges containing this compound. On the basis of quantitative results previously published, both methods have adequate validation parameters since the relative insensitivity of capillary electrophoresis compared with liquid chromatography is not important at the concentration required to be determined following a single simple sample pretreatment.

Anti-Infective Agents↗
PubMedDate not supplied

Activity of potassium channel-blockers in breast cancer.

BACKGROUND: Potassium ion (K+) channels are known to play a key role in breast cancer proliferation. MATERIALS AND METHODS: We investigated the expression of Kv1.3 voltage-gated K+ channels in 60 human breast cancer specimens by immunohistochemistry. The effects of K+ channel-blockers on cellular proliferation were examined in vitro. RESULTS: No immunostaining was observed in 4 normal human breast specimens. Eighteen (30%) breast cancer specimens showed high, 35 (58%) moderate and 7 (12%) low Kv1.3 staining in the epithelial compartment. Minoxidil (K+ channel-opener) stimulated growth of MCF-7 human breast cancer cells (maximal approximately 60% at 10 micrograms/mL). K+ channel-blockers, dequalinium and amiodarone, had marked inhibitory effects on MCF-7 proliferation (> 90% inhibition at 1.5 micrograms/mL). Importantly, amiodarone and dequalinium potentiated the growth-inhibitory effects of tamoxifen on human breast (MCF-7, MDA-MB-231) as well as prostate (PC3, MDA-PCA-2B) and colon (Colo320DM, SW1116) cancer cell lines. CONCLUSION: Investigation of combination therapy with tamoxifen and K+ channel-blockers is warranted.

Amiodarone↗
PubMed1996

On the concept of a bivalent pharmacophore for SKCa channel blockers: synthesis, pharmacological testing, and radioligand binding studies on mono-, bis-, and tris-quinolinium compounds.

The dissociation equilibrium constants (Kd values) of dequalinium (2) and the monoquinolinium compounds 1a and 1b have been determined from competition equilibrium radioligand binding with [125I]apamin on rat brain synaptic plasma membranes (SPMs). Dequalinium binds to the channel with 2 orders of magnitude higher affinity than 1a or 1b, suggesting that both quinolinium groups are needed for potent and selective SKCa channel blockade. The trisquinolinium compound 3 (1,1'-[5-[4-(4- aminoquinolinium-1-yl)but-1-yl]non-4-en-1,9-diyl]-bis-(4- aminoquinolinium)) has been synthesized and tested for inhibition of the afterhyperpolarization of rat sympathetic neurones and on the binding assay. Compound 3 shows approximately one order of magnitude higher potency than 2, being the most potent non-peptidic SKCa channel blocker reported so far (Kd approximately 30 nM). The higher affinity of 3 compared with 2 may be due to direct binding of the third quinolinium group to the channel or may arise from a reduction of the unfavorable entropy of binding via an increase of the "local concentration" of quinolinium groups.

Animals↗
PubMed2002

Expression and activity of potassium ion channels in human prostate cancer.

Four normal and 79 human prostate cancer (Pca) specimens were examined, by immunohistochemistry, for expression of voltage-gated potassium ion channels. Strong immunostaining (for Kv1.3) was observed in the normal and 47% (37/79) of Pca specimens. Twenty-nine percent (23/79) Pca specimens showed moderate and 24% (19/79) displayed low staining. Three potassium channel-openers at a concentration of 10 microg/mL, minoxidil (47.8 microM), 1-Ethyl-2-benzimidazolinone (EBIO) (61.7 microM) and diazoxide (43.3 microM), increased growth of PC3 cells by 30-50%. Potassium channel-blockers, dequalinium, amiodarone and glibenclamide, caused a dose-dependent, growth inhibition of four human Pca cell lines. Apoptosis occurred within 4h of treatment of PC3 cells with dequalinium (0.5 microg/mL, 0.9 microM), amiodarone (5 microg/mL, 7.3 microM) or glibenclamide (50 microg/mL, 0.1mM).

Anti-Arrhythmia Agents↗
PubMed1995

ATP synthase of chloroplasts: selective action of agents binding to F1 on partial reactions of proton transfer in F0.

We studied the basic steps of proton transfer through ATP synthase of chloroplasts, CF0CF1, under conditions of proton slip, a conducting stage in the absence of added nucleotides. On the background of a steady transmembrane pH difference, voltage steps were induced by flashing light. Proton intake, transfer, and release by CF0CF1 were kinetically resolved by spectrophotometric probes. Kinetic disparities between these three steps were observed. Rapid but limited proton intake from the thylakoid lumen and proton release into the medium (tau 1/2 approximately 5 ms) preceded charge transfer across the dielectric barrier in the enzyme (tau 1/2 approximately 30 ms). The saturation behavior under multiple flashes suggested a sequential reaction mechanism. ADP and dequalinium, when bound to subunit beta of the catalytic portion, CF1, blocked different partial reactions involving protons. ADP in the catalytic cleft blocked the electrogenic transfer step, and dequalinium at the adjacent DELSEED sequence on the same subunit blocked the release of protons. Both effects prove a long-range conformational transmission between remote (approximately 10 nm) domains on F1 and on F0. For the normal sequence of events from protons to ATP they suggest a specific action of certain proton-transfer steps on different domains of the catalytic portion.

Binding Sites↗
PubMed2004

Crystal structures of QacR-diamidine complexes reveal additional multidrug-binding modes and a novel mechanism of drug charge neutralization.

The Staphylococcus aureus multidrug-binding protein QacR represses transcription of the plasmid-encoded membrane protein QacA, a multidrug efflux transporter. QacR is induced by multiple structurally dissimilar monovalent and bivalent cationic lipophilic compounds, many of which are effluxed from the cell by QacA via the proton motive force. The multidrug-binding pocket of QacR has been shown to be quite extensive and features several glutamates and multiple aromatic residues. To date, the structure of only one QacR-bivalent cationic drug complex (that of QacR bound to dequalinium) has been determined, and how other longer or shorter bivalent cationic compounds bind is unknown. Here we report the crystal structures of QacR bound to two cytotoxic bivalent diamidines, pentamidine and hexamidine. These compounds are structurally similar, differing by only one methylene carbon in the alkyl chain linker. However, this small difference results in very dissimilar binding modes. Similar to dequalinium, hexamidine spans the multidrug-binding pocket, and its positively charged benzamidine groups are neutralized by residues Glu-57 and Glu-120. Pentamidine binds QacR in a novel fashion whereby one of its benzamidine groups interacts with residue Glu-63, and the other is neutralized by carbonyl and side chain oxygen atoms. Thus, these structures demonstrate that a formal negative charge is not a prerequisite for binding positively charged drugs and underscore the versatility of the QacR and, likely, all multidrug-binding pockets.

Bacterial Proteins↗
PubMed2003

Modulation of small conductance calcium-activated potassium (SK) channels: a new challenge in medicinal chemistry.

Small conductance calcium-activated potassium (SK) channels are found in many types of neurons as well as in some other cell types. These channels are selective for K(+) and open when intracellular Ca(2+) rises to omega 500 nM. In neurons, this occurs during and after an action potential. Activation of SK channels hyperpolarizes the membrane, thus reducing cell excitability for several tens or hundreds of milliseconds. This phenomenon is called a afterhyperpolarization (AHP). Three subtypes of SK channels (SK1, SK2, SK3) have been cloned and exhibit a differential localization in the brain. SK channels may play a role in physiological and pathological conditions. They may be involved in the control of memory and cognition. Moreover, they are heavily expressed in the basal ganglia (in particular in the substantia nigra, pars compacta) and in the limbic system, suggesting that they may modulate motricity and emotional behaviour. Based on these facts, SK channel subtypes may be a suitable target for developing novel therapeutic agents, but more work is needed to validate these targets. Hence, there is a great need for selective ligands. Moreover, although the risk of peripheral side-effects for SK channel modulators appears to be low, some questions remain to be investigated. Currently, different molecules are known as SK channel modulators. Apamin is a very potent peptidic agent; it produces a strong blockade of these targets which is only very slowly reversible and it has limited selectivity. Dequalinium was found to be an effective blocker. Different chemical modulations on the dequalinium structure led to the discovery of highly potent bis-quinolinium derivatives such as UCL 1684. Other bis-(2-amino-benzimidazole) derivatives are in development. On the other hand, quaternary salts of bicuculline were reported to be effective in inhibiting AHPs. More recent developments on structurally-related molecules revealed that methyl-laudanosine is a new interesting tool for exploring SK channel pharmacology. Finally, a family of compounds has been shown to facilitate SK channel opening. Such compounds may be useful in treating disorders involving neuronal hyperexcitability.

Animals↗
PubMed1994

Comparable 30-kDa apamin binding polypeptides may fulfill equivalent roles within putative subtypes of small conductance Ca(2+)-activated K+ channels.

Apamin, a peptide neurotoxin from bee venom, blocks small conductance Ca(2+)-activated K+ channels in central synapses and peripheral tissues. Using 125I-apamin, single classes of high affinity binding sites (Kd 1-3 pM) were identified on plasma membranes from rat, rabbit, guinea pig, and bovine brain and from rabbit, guinea pig, and bovine liver. Binding was sensitive to scyllatoxin, dequalinium, gallamine, and d-tubocurarine but not to charybdotoxin, toxin I, or mast cell degranulating peptide. In contrast, saturable binding of 125I-apamin to rat liver plasma membranes was virtually undetectable, thereby providing a correlation with the ability to measure apamin-sensitive Ca(2+)-activated potassium currents in rabbit and guinea pig hepatocytes but not in rat hepatocytes. In agreement with membrane binding studies, homobifunctional cross-linkers identified apparently identical 33-kDa 125I-apamin binding polypeptides on brain plasma membranes from all species and analogous but distinct polypeptides on plasma membranes from rabbit, guinea pig, and bovine liver. None of these affinity-labeled polypeptides were detectable on plasma membranes from rat liver. Affinity labeling was abolished on both liver and brain membranes by apamin, scyllatoxin, dequalinium, gallamine, and d-tubocurarine. These results indicate that comparable approximately 30-kDa polypeptides may fulfill equivalent functional roles within putative subtypes of apamin-sensitive small conductance Ca(2+)-activated K+ channels.

Animals↗