J B Lansman

University of California, San Francisco, San Francisco, California, United States

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Publications (44)305.3 Total impact

  • Nhi Tan, Jeffry B. Lansman
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    ABSTRACT: Dystrophin is a large, submembrane cytoskeletal protein, an absence of which causes Duchenne muscular dystrophy. Utrophin is a dystrophin homologue found in both muscle and brain whose physiological function is unknown. Recordings of single-channel activity were made from membrane patches on skeletal muscle from mdx, mdx/utrn+/− heterozygotes, and mdx/utrn−/− double knockout mice to investigate the role of these cytoskeletal proteins in mechanosensitive channel gating. We find complex, gene dose-dependent effects of utophin depletion in dystrophin-deficient mdx muscle: 1) increased MS channel open probability, 2) a shift of MS chanel gating to larger pressures, 3) appearance of modal gating of MS channels and small conductance channels, and 4) expression of large conductance MS channels. We suggest a physical model in which utrophin acts as a scaffolding protein that stabilizes lipid microdomains and clusters MS channel subunits. Depletion of utrophin disrupts domain composition in a manner that favors open channel area expansion, as well as allowing diffusion and aggregation of addditional MS channel subunits.This article is protected by copyright. All rights reserved
    The Journal of Physiology 05/2014; · 4.38 Impact Factor
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    ABSTRACT: We recorded the activity of single mechanosensitive (MS) ion channels in skeletal muscle from the mdx mouse, a deletion mutant that lacks the cytoskeletal protein, dystrophin. Experiments were designed to examine the influence of dystrophin, a major component of muscle costameres, on the behavior of single MS cahnnels. In the majority of recordings from cell-attached patches, MS channels have a conductance of ~23 pS. Recordings from some patches, however, showed a smaller conductance channel of ~7-14 pS. Large and small conductance channels were detected in a single patch and showed serial, non-random gating, suggesting different opening levels of a single channel. Analysis of the distribution of current amplitudes within the open channel showed MS channels fluctuate between subconductance levels. MS channels in dystrophic muscle spend ~60% of the time at smaller subconductance levels often failing to reach the fully open level. Applying pressure to the membrane of mdx fibers increases in a graded manner occupancy of the fully open state, while reducing occupancy of subconductance levels. Recordings also show partial openings of MS channels in both wild-type and mdx muscle that fail to reach the fully open state. Partial openings occur at a higher frequency in mdx muscle and reflect occupancy of subconductance levels seen during complete activations. In muscle from mdx/utrn-/- double knockout mice, MS channels also spend more time at subconductance levels than the fully open state. The conductance variability of MS channels may represent gating of a heteromeric protein composed of different channel subunits. The results also show that partial opening and prolonged burst duration are distinct mechanisms that contribute to excess Ca2+ entry in dystrophic muscle.
    The Journal of Physiology 09/2012; · 4.38 Impact Factor
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    ABSTRACT: We recorded the activity of single mechanosensitive (MS) ion channels from membrane patches on single muscle fibers isolated from mice. We investigated the actions of various TRP (transient receptor potential) channel blockers on MS channel activity. 2-aminoethoxydiphenyl borate (2-APB) neither inhibited nor facilitated single channel activity at submillimolar concentrations. The absence of an effect of 2-APB indicates MS channels are not composed purely of TRPC or TRPV1, 2 or 3 proteins. Exposing patches to 1-oleolyl-2-acetyl-sn-glycerol (OAG), a potent activator of TRPC channels, also had no effect on MS channel activity. In addition, flufenamic acid and spermidine had no effect on the activity of single MS channels. By contrast, SKF-96365 and ruthenium red blocked single-channel currents at micromolar concentrations. SKF-96365 produced a rapid block of the open channel current. The blocking rate depended linearly on blocker concentration, while the unblocking rate was independent of concentration, consistent with a simple model of open channel block. A fit to the concentration-dependence of block gave kon = 13 x 10 ( 6) M (-1) s (-1) and koff = 1609 sec (-1) with KD = ~124 µM. Block by ruthenium red was complex, involving both reduction of the amplitude of the single-channel current and increased occupancy of subconductance levels. The reduction in current amplitude with increasing concentration of ruthenium red gave a KD = ~49 µM. The high sensitivity of MS channels to block by ruthenium red suggests MS channels in skeletal muscle contain TRPV subunits. Recordings from skeletal muscle isolated from TRPV4 knockout mice failed to show MS channel activity, consistent with a contribution of TRPV4. In addition, exposure to hypo-osmotic solutions increases opening of MS channels in muscle. Our results provide evidence TRPV4 contributes to MS channels in skeletal muscle.
    Channels (Austin, Tex.) 07/2012; 6(4). · 1.91 Impact Factor
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    Jeffry B Lansman, Alfredo Franco-Obregón
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    ABSTRACT: 1. Mechanosensitive (MS) channels are expressed abundantly in skeletal muscle at all stages of development. In recordings from membrane patches, MS channels are constitutively active at the resting potential. The channels are selective for cations and have a large single-channel conductance (approximately 25 pS in physiological saline) and a high Ca2+ permeability (relative permeability of Ca2+ to K+ (PCa/PK) = 7). 2. Mechanosensitive channel activity recorded from the surface of myotubes from dystrophic mdx mice was substantially greater than the activity recorded from wild-type myotubes. Increased channel activity in the mutant results from the induction in a subpopulation of channels of a novel MS gating mode characterized by markedly prolonged channel openings and inactivation in response to membrane stretch. 3. Membrane stretch or a strong depolarization causes an irreversible switch to the stretch-inactivated gating mode in mdx myotubes. A stretch-induced shift in MS channel gating mode may contribute to stretch-induced elevations in [Ca2+]i during the early stages of disease pathogenesis. 4. Abnormalities of MS channel behaviour are also detected in recordings from patches on flexor digitorum brevis fibres acutely isolated from mdx mice. Mechanosensitive channel opening probability is higher in mdx fibres at all developmental stages. In addition, channel numbers are persistently elevated during postnatal development, failing to undergo a normal process of downregulation during the first 3 postnatal weeks. 5. Two distinct mechanisms may contribute to elevations of [Ca2+]i in dystrophin-deficient skeletal muscle: (i) a membrane stress-dependent switch of MS channels into to a prolonged opening mode; and (ii) a loss of developmental downregulation leading to persistent MS channel expression during postnatal muscle development.
    Clinical and Experimental Pharmacology and Physiology 08/2006; 33(7):649-56. · 2.41 Impact Factor
  • Jeffry B. Lansman, Alfredo Franco-Obregón
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    ABSTRACT: The mdx mouse, a deletion mutant that lacks full-length dystrophin, has been used to investigate the role of the cytoskeleton in mechanosensitive (MS) channel gating. Recordings of activity of single MS channels from mdx muscle show a novel gating mode with dramatically prolonged open times and stretch-inactivated gating. Compared with normal stretch-activated gating, stretch-inactivation occurs at lower pressures (P1/2 = -13 and -36 mm Hg, respectively), but otherwise has a similar pressure-sensitivity as judged by the steepness of the relation between pressure and channel open probability. Stretch-inactivated channels can be induced in some patches by stretching the membrane or by voltage steps to positive potentials. The switch from stretch-activated to stretch-inactivated gating modes in mdx muscle is consistent with a model involving a change in hydrophobic mismatch between the channel protein and adjacent lipid bilayer. One function of dystrophin may be to organize the membrane into stable local microdomains containing specific phospholipids.
    Mechanosensitivity in Cells and Tissues, Edited by Andre Kamkin, Irina Kiseleva, 01/2005; Academia., ISBN: 5769525908
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    Alfredo Franco-Obregón, Jeffry B Lansman
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    ABSTRACT: We studied the effects of membrane stretch and voltage on the gating of single mechanosensitive (MS) channels in myotubes from dystrophin-deficient mdx mice. In earlier studies of MS channels in mdx myotubes, we found a novel class of stretch-inactivated channels. In the present experiments, we used a gentle suction protocol to determine whether seal formation damaged the membrane and altered MS channel gating, since dystrophin-deficiency is known to be associated with an increased susceptibility to mechanically induced damage. In some recordings from mdx myotubes, MS channel open probability gradually increased to levels approaching unity following seal formation. In these recordings, channels remained open for the duration of the recording. In other recordings, MS channel open probability remained low after seal formation and applying weak suction evoked conventional stretch-activated gating. Applying strong suction or very positive voltages, however, caused some channels to enter a high open probability gating mode. The shift to a high open probability gating mode coincided with the appearance of stretch-inactivated gating. These findings suggested that mechanical stimulation altered the mechanical properties of the patch causing some MS channels to enter a novel gating mode. In support of this idea, stretch-activated and stretch-inactivated channels were not detected in the same membrane patch and channel inactivation occurred at lower pressures than activation (P(1/2,) = -13 and -26.5 mmHg, respectively). Other experiments showed that stretch-inactivated gating was not due to a simple loss of MS channel activity from a non-random process such as vesiculation or bleb formation: channel inactivation by suction was readily reversible, stable over tens of minutes, and followed the predictions of the binomial theorem for independent, randomly gating channels. In addition, the voltage-dependent gating of stretch-inactivated channels was similar to that of stretch-activated channels. The results show that MS channels in dystrophin-deficient muscle exist in two distinct gating modes and that mechanical stimuli cause an irreversible conversion between modes. We discuss possible mechanisms for the changes in MS channel gating in relation to the known cytoskeletal abnormalities of mdx muscle and its possible implications for the pathogenesis of Duchenne dystrophy.
    The Journal of Physiology 04/2002; 539(Pt 2):391-407. · 4.38 Impact Factor
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    P Chavis, L Fagni, J B Lansman, J Bockaert
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    ABSTRACT: In skeletal muscle, L-type Ca2+ channels act as voltage sensors to control ryanodine-sensitive Ca2+ channels in the sarcoplasmic reticulum. It has recently been demonstrated that these ryanodine receptors generate a retrograde signal that modifies L-type Ca2+ -channel activity. Here we demonstrate a tight functional coupling between ryanodine receptors and L-type Ca2+ channel in neurons. In cerebellar granule cells, activation of the type-1 metabotropic glutamate receptor (mGluR1) induced a large, oscillating increase of the L-type Ba2+ current. Activation occurred independently of inositol 1,4,5-trisphosphate and classical protein kinases, but was mimicked by caffeine and blocked by ryanodine. The kinetics of this blockade were dependent on the frequency of Ba2+ current stimulation. Both mGluR1 and caffeine-induced increase in L-type Ca2+ -channel activity persisted in inside-out membrane patches. In these excised patches, ryanodine suppressed both the mGluR1- and caffeine-activated L-type Ca2+ channels. These results demonstrate a novel mechanism for Ca2+ -channel modulation in neurons.
    Nature 09/1996; 382(6593):719-22. · 38.60 Impact Factor
  • H R Parri, J B Lansman
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    ABSTRACT: The contribution of pharmacologically distinct Ca2+ channels to prepulse-induced facilitation was studied in mouse cerebellar granule cells. Ca2+ channel facilitation was measured as the percentage increase in the whole-cell current recorded during a test pulse before and after it was paired with a positive prepulse. The amount of facilitation was small in recordings made during the first few days in tissue culture but increased substantially after 1 week. L-type channels accounted for the largest proportion of facilitation in 1-week-old cells (60-70%), whereas N-type channels contributed very little (approximately 3%). The toxins omega-agatoxin IVa or omega-conotoxin MVIIC (after block of N-, L-, and P-type channels) each blocked a small percentage of facilitation (approximately 12 and 14%, respectively). Perfusion of cells with GTP-gamma-S enhanced the facilitation of N-type channels, whereas it inhibited of L-type channels. During development in vitro, the contribution of L-type channels to the whole-cell current decreased. Single-channel recordings showed the presence of 10 and 15 pS L-type Ca2+ channels in 1-d-old cells. After 1 week in culture, a approximately 25 pS L-type channel dominated recordings from cell-attached patches. Positive prepulses increased the activity of the 25 pS channel but not of the smaller conductance channels. The expression of Ca(2+) channel facilitation during development may contribute to changes in excitability that allow frequency-dependent Ca(2+) influx during the period of active synaptogenesis
    Journal of Neuroscience 09/1996; 16(16):4890-902. · 6.91 Impact Factor
  • P. Chavis, L. Fagni, J. B. Lansman, J. Bockaert
    Neuropharmacology 06/1996; 35(6). · 4.11 Impact Factor
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    B D Winegar, C M Haws, J B Lansman
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    ABSTRACT: The activity of single mechanosensitive channels was recorded from cell-attached patches on acutely isolated skeletal muscle fibers from the mouse. The experiments were designed to investigate the mechanism of channel block produced by externally applied aminoglycoside antibiotics. Neomycin and other aminoglycosides reduced the amplitude of the single-channel current at negative membrane potentials. The block was concentration-dependent, with a half-maximal concentration of approximately 200 microM. At high drug concentrations, however, block was incomplete with roughly one third of the current remaining unblocked. Neomycin also caused the channel to fluctuate between the open state and a subconductance level that was also roughly one third the amplitude of the fully open level. An analysis of the kinetics of the subconductance fluctuations was consistent with a bimolecular reaction between an aminoglycoside molecule and the open channel (kon = approximately 1 x 10(6) M-1s-1 and koff = approximately 400 s-1 at -60 mV). Increasing the external pH reduced both the rapid block of the open channel and the frequency of the subconductance fluctuations, as if both blocking actions were produced by a single active drug species with a pKa = approximately 7.5. The results are interpreted in terms of a mechanism in which an aminoglycoside molecule partially occludes ion flow through the channel pore.
    The Journal of General Physiology 04/1996; 107(3):433-43. · 4.73 Impact Factor
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    P A Slesinger, J B Lansman
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    ABSTRACT: 1. We recorded the activity of single L-type Ca2+ channels from cell-attached patches on mouse cerebellar granule cells. The experiments investigated the mechanism of channel reopening at negative membrane potentials following a strong depolarization. 2. L-type channels that reopened following a strong depolarization showed a wide distribution of single-channel conductances, which ranged from 16 to 28 pS in the presence of 90 mM Ba2+. 3. The distribution of the latencies before reopening was fitted as the sum of two exponential components with time constants tau f approximately 1 and tau s approximately 12 ms at -70 mV. Hyperpolarization reduced the time constant of the slower component approximately e-fold per 43 mV, but had no effect on the faster component. 4. Raising the concentration of external Ba2+ reduced the time constant of the slower component of the reopening latency without altering the fast component. The time constant of the slow component was approximately 27 ms in 10 mM Ba2+ and decreased to 12 ms in 90 mM Ba2+ at -70 mV. The relation between the time constant and external Ba2+ saturated with an apparent KD of approximately 20 mM. 5. The distribution of reopening times was best fitted as the sum of two exponential components with time constants tau f approximately 0.5 ms and tau s approximately 4.5 ms at -70 mV. The conditional latencies before reopening into either the short or long open state were indistinguishable. 6. The results are consistent with the idea that a positively charged blocker occludes the pore during depolarization and channels reopen as the blocker dissociates following repolarization to negative potentials.
    The Journal of Physiology 04/1996; 491 ( Pt 2):335-45. · 4.38 Impact Factor
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    C M Haws, B D Winegar, J B Lansman
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    ABSTRACT: The activity of single L-type Ca2+ channels was recorded from cell-attached patches on acutely isolated skeletal muscle fibers from the mouse. The experiments were concerned with the mechanism by which aminoglycoside antibiotics inhibit ion flow through the channel. Aminoglycosides produced discrete fluctuations in the single-channel current when added to the external solution. The blocking kinetics could be described as a simple bimolecular reaction between an aminoglycoside molecule and the open channel. The blocking rate was found to be increased when either the membrane potential was made more negative or the concentration of external permeant ion was reduced. Both of these effects are consistent with a blocking site that is located within the channel pore. Other features of block, however, were incompatible with a simple pore blocking mechanism. Hyperpolarization enhanced the rate of unblocking, even though an aminoglycoside molecule must dissociate from its binding site in the channel toward the external solution against the membrane field. Raising the external permeant ion concentration also enhanced the rate of unblocking. This latter finding suggests that aminglycoside affinity is modified by repulsive interactions that arise when the pore is simultaneously occupied by a permeant ion and an aminoglycoside molecule.
    The Journal of General Physiology 04/1996; 107(3):421-32. · 4.73 Impact Factor
  • A Franco-Obregón, J B Lansman
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    ABSTRACT: Single-channel activity was recorded from cell-attached patches on skeletal muscle cells isolated from wild-type mice and from mice carrying the dy or mdx mutations. Spontaneous openings of the nicotinic acetylcholine receptor channel (nAChR) were detected in virtually all recordings from either dy/dy or dy/+ myotubes, but only infrequently from wild-type or mdx myotubes. Spontaneous openings were also present in most recordings from undifferentiated myoblasts from all of the mouse strains studied. The biophysical properties of the spontaneous activity were similar to those of the embryonic form of the nAChR in the presence of acetylcholine (ACh). Examination of the single-channel currents evoked by low concentrations of ACh showed a reduced sensitivity to the agonist in the dystrophic dy and mdx myotubes, but not in wild-type myotubes. The results suggest that alterations in nAChR function are associated with the pathogenesis of muscular dystrophy in the dy mouse.
    Journal of Neuroscience Research 12/1995; 42(4):452-8. · 2.97 Impact Factor
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    P Chavis, L Fagni, J Bockaert, J B Lansman
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    ABSTRACT: We investigated the mechanisms by which metabotropic glutamate receptors (mGluRs) modulate specific Ca2+ channels in cerebellar granule cells. A large fraction of the current in granule cells is carried by L- and Q-type Ca2+ channels (about 26% each), whereas N- and P-type contribute proportionally less to the global current (9 and 15%, respectively). l-Aminocyclopentane-dicarboxylate (t-ACPD), (2S,3S,4S)-alpha-(carboxycyclopropyl)-glycine (L-CCGI) and (S)-4-carboxy-3-hydroxyphenylglycine [(S)-4C3HPG], but not L(+)-2-amino-4-phosphonobutyrate (L-AP4) reduced the Ca2+ current amplitude. The t-ACPD-induced inhibition was fully antagonized by (+/-)-methyl-4-carboxyphenylglycine [(+/-)-MCPG] and blocked by pertussis toxin (PTX). These results are consistent with inhibitory response mediated by mGluR2/R3. The use of specific Ca2+ channel blockers provided evidence that mGluR2/R3 inhibited both L- and N-type Ca2+ currents. In PTX-treated cells, Glu or t-ACPD, but not L-CCGI or L-AP4, increased the Ca2+ current. Consistent with the activation of mGluR1, the antagonists (+)-MCPG and (S)-4C3HPG prevented the facilitation of Ca2+ current produced by t-ACPD. The mGluR1-activated facilitation was completely blocked by nimodipine, indicating that L-type Ca2+ currents were selectively potentiated.
    Neuropharmacology 09/1995; 34(8):929-37. · 4.11 Impact Factor
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    T R Elam, J B Lansman
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    ABSTRACT: We have studied the role of Mg2+ in the inactivation of inwardly rectifying K+ channels in vascular endothelial cells. Inactivation was largely eliminated in Mg(2+)-free external solutions and the extent of inactivation was increased by raising Mg2+o. The dose-response relation for the reduction of channel open probability showed that Mg2+o binds to a site (KD = approximately 25 microM at -160 mV) that senses approximately 38% of the potential drop from the external membrane surface. Analysis of the single-channel kinetics showed that Mg2+ produced a class of long-lived closures that separated bursts of openings. Raising Mg2+o reduced the burst duration, but less than expected for an open-channel blocking mechanism. The effects of Mg2+o are antagonized by K+o in manner which suggests that K+ competes with Mg2+ for the inactivation site. Mg2+o also reduced the amplitude of the single-channel current at millimolar concentrations by a rapid block of the open channel. A mechanism is proposed in which Mg2+ binds to the closed channel during hyperpolarization and prevents it from opening until it is occupied by K+.
    The Journal of General Physiology 05/1995; 105(4):463-84. · 4.73 Impact Factor
  • A. Franco-Obregón, J.B Lansman
    Journal of Neuroscience Research 01/1995; 42:452. · 2.97 Impact Factor
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    A Franco-Obregón, J B Lansman
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    ABSTRACT: 1. We examined the activity of single mechanosensitive ion channels in recordings from cell-attached patches on myoblasts, differentiated myotubes and acutely isolated skeletal muscle fibres from wild-type and mdx and dy mutant mice. The experiments were concerned with the role of these channels in the pathophysiology of muscular dystrophy. 2. The predominant form of channel activity recorded with physiological saline in the patch electrode arose from an approximately 25 pS mechanosensitive ion channel. Channel activity was similar in undifferentiated myoblasts isolated from all three strains of mice. By contrast, channel activity in mdx myotubes was approximately 3-4 times greater than in either wild-type or dy myotubes and arose from a novel mode of mechanosensitive gating. 3. Single mechanosensitive channels in acutely isolated flexor digitorum brevis fibres had properties indistinguishable from those of muscle cells grown in tissue culture. The channel open probability in mdx fibres was approximately 2 times greater than the activity recorded from wild-type fibres. The overall level of activity in fibres, however, was roughly an order of magnitude smaller than in myoblasts or myotubes. 4. Histological examination of the flexor digitorum brevis fibres from mdx mice showed no evidence of myonecrosis or regenerating fibres, suggesting that the elevated channel activity in dystrophin-deficient muscle precedes the onset of fibre degeneration. 5. An early step in the dystrophic process of the mdx mouse, which leads to pathophysiological Ca2+ entry, may be an alteration in the mechanisms that regulate mechanosensitive ion channel activity.
    The Journal of Physiology 01/1995; 481 ( Pt 2):299-309. · 4.38 Impact Factor
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    C M Haws, P A Slesinger, J B Lansman
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    ABSTRACT: The inhibition of high-threshold Ca2+ channel currents by activated G-proteins was studied in mouse cerebellar granule cells making use of the hydrolysis-resistant GTP analog GTP-gamma-S. When individual granule cells were internally dialyzed with GTP-gamma-S, the high-threshold Ca2+ current decreased to approximately 20% of its initial value within approximately 2 min. The GTP-gamma-S-resistant current was reduced further by the subsequent addition of either omega-conotoxin or dihydropyridine antagonist, indicating that both N- and L-type Ca2+ channels carried the remaining current. Continuous exposure to the dihydropyridine agonist +(S)-202-791 caused a rapid increase in the GTP-gamma-S-resistant current. The L-type current evoked by the agonist subsequently decreased to the level observed prior to adding the drug following a time course similar to the initial inhibition of the total high-threshold current. A second application of the drug at a later time failed to increase the current a second time, indicating a persistent blockade of the agonist-evoked L-current. Pretreating cells with pertussis toxin prevented the initial inhibition of the total whole-cell Ca2+ channel current as well as the subsequent inhibition of the agonist-evoked L-current. The results show that a pertussis toxin-sensitive G-protein produces a persistent inhibition of L-type Ca2+ channels in these central neurons.
    Journal of Neuroscience 04/1993; 13(3):1148-56. · 6.91 Impact Factor
  • Paul A. Slesinger, Jeffry B. Lansman
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    ABSTRACT: Recordings of single-channel activity from cerebellar granule cells show that a component of Ca2+ entry flows through L-type Ca2+ channels that are closed at negative membrane potentials following a strong depolarization, but then open after a delay. The delayed openings can be explained if membrane depolarization drives Ca2+ channels into an inactivated state and some channels return to rest through the open state after repolarization. Whole-cell recordings show that the charge carried by Ca2+ during the tail increases as inactivation progresses, whereas the current during the voltage step decreases. Voltage-dependent inactivation may be a general mechanism in central neurons for enhancing Ca2+ entry by delaying it until after repolarization, when the driving force for ion entry is large. Modifying the rate and extent of inactivation would have large effects on Ca2+ entry through those channels that recover from inactivation by passing through the open state.
    Neuron 12/1991; 7(5):755-62. · 15.77 Impact Factor
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    J B Lansman, A Franco
    Journal of Muscle Research and Cell Motility 11/1991; 12(5):409-11. · 1.36 Impact Factor

Publication Stats

3k Citations
305.30 Total Impact Points

Institutions

  • 1991–2014
    • University of California, San Francisco
      • • Division of Hospital Medicine
      • • Department of Cellular and Molecular Pharmacology
      San Francisco, California, United States
  • 1987
    • University of California, Los Angeles
      • Department of Medicine
      Los Angeles, CA, United States