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Biomedical subjects

B E Ehrlich

Publications and source records attributed to B E Ehrlich.

At least 55 records · Page 3Linked to original sources
PubMed1988

Paramecium calcium channels are blocked by a family of calmodulin antagonists.

Although the voltage-sensitive Ca channel present in Paramecium has been subjected to detailed physiological and genetic analysis, no organic ligands have been described that block this channel with high affinity and that ultimately can be used to identify channel components. Based on a previous observation that the naphthalene sulfonamide calmodulin antagonist W-7 can block Paramecium Ca channels at high concentration, we have synthesized analogs of W-7 that block these channels at concentrations of less than 1 microM. The effectiveness of these compounds was tested both by a sensitive behavioral assay and on Ca channels that had been incorporated into planar lipid bilayers. Despite the fact that these compounds are effective Paramecium calmodulin antagonists, two independent lines of evidence suggest that W-7 and its analogs block the Ca channel by a mechanism that is independent of their action on calmodulin. In addition, the sensitivity to W-7 or dihydropyridines of Ca channels present in a number of eukaryotic phyla has been used to identify similarities in Ca channels from widely diverse organisms. It appears that the pharmacological specificity provides a means to group Ca channels.

Animals↗
PubMed1986

Incorporation of calcium channels from cardiac sarcolemmal membrane vesicles into planar lipid bilayers.

When purified porcine cardiac sarcolemmal membrane vesicles are incorporated into planar lipid bilayers formed at the tip of patch electrode pipettes, individual divalent cation channels can be monitored. Channel activity is increased in the presence of the Ca2+ channel agonist Bay K 8644, is voltage dependent, and selects for divalent cations over anions. The activity does not inactivate because it is maintained during prolonged depolarizations. Determination of divalent cation selectivity from the reversal potential of single-channel currents indicates a relative permeability ratio for Ba/Ca/Mg of 1:0.45:0.08. Mean channel conductance in 0.1 M Ba2+/0.01 M Mg2+ is 8 pS. Channels are reversibly blocked by the Ca2+ channel inhibitor nitrendipine, and inhibition can be competitively antagonized by Bay K 8644. Binding studies with 3H-labeled D-600 demonstrate the presence of high-affinity receptors for D-600 in sarcolemmal membranes (Kd = 6.4 X 10(-9) M; Bmax = 3 pmol per mg of protein). In addition, experiments with resolved D-600 stereoisomers indicate that (-)D-600 is at least 25-fold more potent than (+)D-600 in competing for this aralkyl amine receptor. Consistent with this, (-)D-600 is much more effective than the (+) isomer in inhibiting bilayer-incorporated channels. These results demonstrate that the divalent cation channel that has been reconstituted in planar lipid bilayers possesses many of the characteristics of voltage-regulated Ca2+ channels in heart and suggest that receptors for Ca2+ entry blockers are functionally associated with this channel.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1985

Channels formed by botulinum, tetanus, and diphtheria toxins in planar lipid bilayers: relevance to translocation of proteins across membranes.

The heavy chains of both botulinum neurotoxin type B and tetanus toxin form channels in planar bilayer membranes. These channels have pH-dependent and voltage-dependent properties that are remarkably similar to those previously described for diphtheria toxin. Selectivity experiments with anions and cations show that the channels formed by the heavy chains of all three toxins are large; thus, these channels could serve as "tunnel proteins" for translocation of active peptide fragments. These findings support the hypothesis that the active fragments of botulinum neurotoxin and tetanus toxin, like that of diphtheria toxin, are translocated across the membranes of acidic vesicles.

Botulinum Toxins↗
PubMed1984

Lithium transport across squid axon membrane.

This paper describes the pathways for lithium transport across the axonal membrane of squid. We were able to show that the membrane of this classical neuronal preparation possesses the lithium transport mechanisms previously identified in red blood cells. It is now possible to predict that the lithium treatment-induced changes in choline and lithium transport that have been observed in red blood cells of manic depressive patients also occur in nerve membrane.

Animals↗
PubMed1984

Voltage-dependent calcium channels from Paramecium cilia incorporated into planar lipid bilayers.

Two different divalent cation-selective channels from Paramecium cilia were incorporated into planar lipid bilayers. Both channels were much more permeable to divalent than univalent cations, and one of them discriminated significantly among the divalent cations. The selectivity and voltage dependence of the latter channel are comparable to those of voltage-dependent calcium channels found in a variety of cells. A combined biochemical, biophysical, and genetic study of calcium channels is now possible.

Barium↗
PubMed1984

Bacterial rhodopsins monitored with fluorescent dyes in vesicles and in vivo.

Three retinal-containing pigments have been detected in Halobacterium halobium membranes: bacteriorhodopsin (bR), halorhodopsin (hR), and slow-cycling rhodopsin (sR). The first two hyperpolarize the cell membrane by electrogenic transport of H+ and Cl-, respectively. The third pigment, sR, may be a photosensory receptor since mutants lacking bR and hR retain their retinal-dependent phototaxis responses. We monitored light-induced changes in fluorescence of several voltage-sensitive dyes in cells and membrane vesicles. Red light-induced potential changes generated by bR and hR were similar to signals described previously. Signals generated by hR could be identified using four criteria: wavelength dependence, Cl- dependence, shunting by valinomycin and K+, and the absence of these signals in hR-deficient mutants. The absence (detection limit approximately 0.5 mV) of hyperpolarization signals in bR-hR-sR+ vesicles and cells shows that sR photochemical reactions are nonelectrogenic. Two signals independent of bR and hR were measured: blue light caused a decrease and red light an increase in dye fluorescence. Both signals appear to derive from sR on the basis of their retinal-dependence and action spectra. In a retinal-deficient mutant strain (Flx3R), both sR signals appeared after addition of all-trans retinal. In this strain retinal also restores phototaxis sensitivity within the same time scale. The retinal concentration dependence for all four parameters monitored--the attractant (red) and repellent (blue) phototaxis, and the red light and blue light-induced fluorescence signals--is the same. This correlation is consistent with the hypothesis that both attractant and repellent responses are mediated by sR, as suggested by Bogomolni and Spudich (Proc. Natl. Acad. Sci. USA. 79:6250-6254 (1982)).

Bacteriorhodopsins↗
PubMed1984

Lithium concentration in the muscle compartment of manic-depressive patients during lithium therapy.

Pharmacokinetic (PK) techniques were used to study the effect of lithium (Li+) on Li+ fluxes and concentrations in body compartments of manic-depressives. Patients not yet on Li+ therapy were similar to normal controls in all parameters. Comparison of patients before and during chronic Li+ therapy showed no effect of Li+ therapy on intestinal absorption and renal excretion of Li+. The calculated erythrocyte (RBC)-to-plasma Li+ concentration ratio increased with Li+ therapy, as already known from direct measurements. The calculated muscle-to-plasma Li+ concentration ratio was 6-8 times higher than the RBC ratio, and increased from 1.8 to 4.2 with Li+ therapy. The higher Li+ concentration in human muscle compared to RBC is attributed to muscle's higher inside-negative resting potential, and may underlie side effects that arise in muscle from Li+ therapy. The discrepancy between the observed muscle-to-plasma ratio and that predicted for a passively distributed ion is attributed to extrusion by a countertransport process, and the increase in the observed ratio with Li+ therapy is attributed to inhibition of countertransport, as already established for RBC. Since muscle resembles nerve as an excitable cell, muscle Li+ warrants evaluation as a predictor of therapeutic response and side effects during Li+ therapy.

Bipolar Disorder↗
PubMed1983

Lithium absorption in tight and leaky segments of intestine.

There is significant absorption of Li+ by human jejunum and ileum, but negligible absorption by human colon. Thus, a proximal-to-distal gradient of decreasing Li+ absorption and increasing junctional tightness exists in intestine as well as in renal tubule. For six leaky epithelia the relative permeabilities of K+, Na+, and Li+ by the junctional route are in the sequence PK greater than PNa greater than PLi and all fall within a factor of 2.5. In contrast, for tight epithelia PLi approximately PNa much greater than PK in the amiloride-sensitive channel of the apical membrane, but PK much greater than PLi approximately PNa in the basolateral membrane. The ability of several tight epithelia to sustain nonzero transepithelial Li+ absorption despite this basolateral barrier may be due to Na+/Li+ countertransport at the basolateral membrane, resulting in secondary active transport of Li+ across the epithelium.

Adult↗
PubMed1983

Lithium's inhibition of erythrocyte cation countertransport involves a slow process in the erythrocyte.

Chronic administration of lithium (Li+) to human subjects results in reduction of Li+/Na+ countertransport in their erythrocytes (RBC). The time course of development of inhibition is much slower than one would expect for an immediate effect of Li+ on the RBC membrane. Possible explanations include pharmacokinetic delays, a mediating humoral agent, and a slow process in the RBC. To discriminate among these possibilities, we incubated human RBC in sterile culture by the method of Freedman (Freedman, J.C. 1983. J. Membrane Biol. 75:225--231), which permits much longer incubations than other methods. As gauged by eight measures, the incubated RBC remain viable for two weeks. Small changes in intracellular concentrations with time during incubation are in the same direction as the changes associated with natural aging of RBC in vivo, except for a rise in ATP and related cation shifts during the first few days of incubation. Treatment of incubated RBC with 2 mM Li+ inhibits countertransport by 48% without affecting Li+ leak efflux. The inhibition develops slowly: it is half-maximal after 1--2 days and maximal by 4--7 days. Differences between in vivo results and our incubated cells in the time course of inhibition are as expected from the pharmacokinetic delays operating in vivo. The inhibition is reversible on removing Li+. Li+ inhibits countertransport similarly slowly and to a similar degree from inside the RBC and from outside. Hence the slow time course of inhibition in vivo is not due to a humoral factor or to the time required for intracellular Li+ accumulation and is only partly due to pharmacokinetic delays. The delay must involve an unidentified slow process at the level of the RBC.

Biological Transport, Active↗
PubMed1982

Choline and PAH transport across blood-CSF barriers: the effect of lithium.

The components of the blood-CSF barrier responsible for the transport of p-aminohippuric acid (PAH) and choline from CSF to blood were identified using in vitro preparations of frog choroid plexus and arachnoid membranes. Choline was transported out of CSF across the arachnoid, while PAH was transported out across the choroid plexus. Probenecid and ouabain blocked both processes. The effect of Li on these transport processes was tested by the addition of 5 mM LiCl to the incubation media. Li increased, by a factor of two, choline transport across the arachnoid, but there was no effect of Li on PAH transport across the plexus. Lithium was passively transported across the choroid plexus, and we suggest that the major transport pathway is through the tight junctions. The steady-state distribution of Li between the choroidal epithelium and the incubation medium was only half that expected for passive distribution. This suggests the existence of sodium/lithium countertransport in these epithelial cell membranes.

Aminohippuric Acids↗
PubMed1981

Variable effect of lithium on canine pancreatic polypeptide and gastrin release by a meal or bombesin.

Lithium is a cation which has central nervous system effects and is able to interfere with both the release and action of polypeptide hormones. We examined its effect on basal and stimulated plasma gastrin and pancreatic polypeptide (PP) levels in 4 dogs with chronic gastric fistulas. Gastrin and PP release were stimulated by a meal or bombesin nonapeptide infusion (1.2 microgram kg-1h-1). The studies were repeated 24h and 14 days after lithium administration (600 mg/12 h) orally. Basal plasma lithium values were undetectable and rose to 0.9 /+- 0.2 mmol l-1 in the acute and 1.0 +/- 0.2 mmol l-1 in the chronically treated animals. The dogs did not have any discernible side effects. Basal plasma gastrin was 14 +/- 4 fmol ml -1 and was not significantly altered by either 1 or 14 days Li+( p greater than 0.05). Gastrin release stimulated by either a meal or bombesin was not significantly decreased by acute or chronic Li+ administration . Acute lithium administration produced a slight but significant increase in meal-stimulated gastrin (p less than 0.01). Neither acute nor chronic lithium administration altered bombesin stimulated gastric acid secretin (p greater than 0.05). Basal PP levels were 24 +/- 7 fmol ml-1 and not significantly altered by 1 or 14 days Li+ administration. Both acute and chronic Li+ inhibited PP release by bombesin in the first 30-min period of the study (p less than 0.01). 14 days Li+ significantly inhibited both first and second hour PP responses to a meal (p less than 0.01). The mechanism of the cationic modification of the release of pancreatic polypeptide requires further elucidation.

Animals↗
PubMed1980

Lithium pharmacokinetics: single-dose experiments and analysis using a physiological model.

The kinetics of lithium (Li+) distribution after a single dose was studied in healthy human subjects. Experiments were performed by simultaneously following changes of Li+ concentration in plasma, erythrocytes (RBC), and urine. The data were fitted by a simple but physiologically realistic model, so that extracted rate constants could be assigned to real body compartments and compared with independent measurements of cellular transport characteristics. The extracted rate constants were used to calculate steady-state cell-to-plasma Li+ ratios for RBC and for inaccessible cells (mainly muscle). In both cell types, the intracellular Li+ concentration is far below electrochemical equilibrium. This finding suggests that the Li+ countertransport efflux mechanism of RBC may be shared with muscle. We also present evidence for a circadian rhythm in Li+ excretion that parallels the daily cycle of Na+ and K+ excretion.

Adult↗