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PubMed2000

Dynamics of dendritic calcium transients evoked by quantal release at excitatory hippocampal synapses.

Synaptic N-methyl-D-aspartate (NMDA) receptors detect coincident pre- and postsynaptic activity and play a critical role in triggering changes in synaptic strength at central synapses. Despite intensive study of synaptic plasticity, relatively little is known about the magnitude and duration of calcium accumulation caused by unitary events at individual synapses. We used fluorescence imaging to detect NMDA receptor-mediated miniature synaptic calcium transients (MSCTs) caused by spontaneous release of synaptic vesicles in dendrites of cultured hippocampal neurons. MSCTs originated focally in dendritic regions <1 microm in length and decayed with a time constant of 0.35 +/- 0.03 s. Multiple occurrences of MSCTs recorded at single sites had fluctuating amplitudes, with a coefficient of variation of 0.34. From the reduction in the spatial spread of MSCTs with decreasing concentration of indicator dye, we estimated that the dominant endogenous calcium buffer in dendrites is relatively immobile (diffusion coefficient between 10 and 50 microm(2)/s). We conclude that calcium rise caused by spontaneous quantal synaptic NMDA receptor activation (i) is variable, (ii) lasts for a time period briefer than previous measurements indicate, and (iii) is confined by endogenous calcium buffers to local dendritic regions even when synapses are not on spines.

Aniline Compounds↗
PubMed1997

Cyclic ADP-ribose enhances coupling between voltage-gated Ca2+ entry and intracellular Ca2+ release.

Ca2+ release from intracellular stores can be activated in neurons by influx of Ca2+ through voltage-gated Ca2+ channels. This process, called Ca2+-induced Ca2+ release, relies on the properties of the ryanodine receptor and represents a mechanism by which Ca2+ influx during neuronal activity can be amplified into large intracellular Ca2+ signals. In a differentiated neuroblastoma cell line, we show that caffeine, a pharmacological activator of the ryanodine receptor, released Ca2+ from intracellular stores in a Ca2+-dependent and ryanodine-sensitive manner. The pyridine nucleotide, cyclic ADP-ribose, thought to be an endogenous modulator of ryanodine receptors also amplified Ca2+-induced Ca2+ release in these neurons. Cyclic ADP-ribose enhanced the total cytoplasmic Ca2+ levels during controlled Ca2+ influx through voltage gated channels, in a concentration-dependent and ryanodine-sensitive manner and also increased the sensitivity with which a small amount of Ca2+ influx could trigger additional release from the ryanodine-sensitive intracellular Ca2+ stores. Single cell imaging showed that following the Ca2+ influx, cyclic ADP-ribose enhanced the spatial spread of the Ca2+ signal from the edge of the cell into its center. These powerful actions suggest a role for cyclic ADP-ribose in the functional coupling of neuronal depolarization, Ca2+ entry, and global intracellular Ca2+ signaling.

Adenosine Diphosphate Ribose↗
PubMed1963

CHOLINESTERASE IN DENERVATED END PLATES AND MUSCLE FIBRES.

Parallel studies were made of cholinesterase activities and localizations in denervated rat and rabbit gastrocnemius muscle. Koelle's histochemical reaction was used for demonstrating the localization of cholinesterases. Enzyme activities in whole sliced muscle were measured by electrometric titration. The Cartesian ampulla-diver technique was used for cholinesterase activity determinations in end plate regions or in small pieces of the muscle fibre itself. No changes in the activity of cholinesterases (ChE) were found in the whole denervated muscle which would account for its chemical supersensitivity. The ChE distribution pattern was changed so that the end plate region became less active in the denervated muscle than in the normal one. The decrease in ChE activity in the end plates seems to be largely compensated for by an increase of this enzyme elsewhere in the muscle. A possible connection between the spatial spread of cholinesterase activity and the enlargement of the acetylcholine-sensitive surface is discussed.

Acetylcholine↗
PubMed1995

Caffeine- and ryanodine-sensitive Ca(2+)-induced Ca2+ release from the endoplasmic reticulum in honeybee photoreceptors.

Light stimulation of invertebrate microvillar photoreceptors causes a large rapid elevation in Cai, shown previously to modulate the adaptational state of the cells. Cai rises, at least in part, as a result of Ins(1,4,5)P3-induced Ca2+ release from the submicrovillar endoplasmic reticulum (ER). Here, we provide evidence for Ca(2+)-induced Ca2+ release (CICR) in an insect photoreceptor. In situ microphotometric measurements of Ca2+ fluxes across the ER membrane in permeabilized slices of drone bee retina show that (a) caffeine induces Ca2+ release from the ER; (b) caffeine and Ins(1,4,5)P3 open distinct Ca2+ release pathways because only caffeine-induced Ca2+ release is ryanodine sensitive and heparin insensitive, and because caffeine and Ins(1,4,5)P3 have additive effects on the rate of Ca2+ release; (c) Ca2+ itself stimulates release of Ca2+ via a ryanodine-sensitive pathway; and (d) cADPR is ineffective in releasing Ca2+. Microfluorometric intracellular Ca2+ measurements with fluo-3 indicate that caffeine induces a persistent elevation in Cai. Electrophysiological recordings demonstrate that caffeine mimics all aspects of Ca(2+)-mediated facilitation and adaptation in drone photoreceptors. We conclude that the ER in drone photoreceptors contains, in addition to the Ins(1,4,5)P3-sensitive release pathway, a CICR pathway that meets key pharmacological criteria for a ryanodine receptor. Coexpression of both release mechanisms could be required for the production of rapid light-induced Ca2+ elevations, because Ca2+ amplifies its own release through both pathways by a positive feedback. CICR may also mediate the spatial spread of Ca2+ release from the submicrovillar ER toward more remote ER subregions, thereby activating Ca(2+)-sensitive cell processes that are not directly involved in phototransduction.

Adenosine Diphosphate Ribose↗
PubMed1956

Changes in membrane characteristics of heart muscle during inhibition.

Membrane characteristics were studied in isolated muscle strands from auricles of frogs using the "square pulse" technique. Changes in the time course and spatial spread of subthreshold electrotonic potentials were measured. If acetylcholine is applied in concentrations which cause slowing or stoppage of the heart beat, the following changes are produced: (a) the length constant (lambda) of the membrane is reduced, (b) the time constant is shortened. The effects are reversible and increase with acetylcholine concentration. The membrane changes caused by acetylcholine dimmish with time. It is concluded that during acetylcholine inhibition, as well as during vagal inhibition, the conductance of the muscle membrane is increased. Appreciable changes in the resting membrane potential need not accompany inhibition.

Acetylcholine↗
PubMed2005

Resource-dependent dispersal and the speed of biological invasions.

Many mobile organisms exhibit resource-dependent movement in which movement rates adjust to changes in local resource densities through changes in either the probability of moving or the distance moved. Such changes may have important consequences for invasions because reductions in resources behind an invasion front may cause higher dispersal while simultaneously reducing population growth behind the front and thus lowering the number of dispersers. Intuiting how the interplay between population growth and dispersal affects invasions is difficult without mathematical models, yet most models assume dispersal rates are constant. Here we present spatial-spread models that allow for consumer-resource interactions and resource-dependent dispersal. Our results show that when resources affect the probability of dispersal, then the invasion dynamics are no different than if resources did not affect dispersal. When resources instead affect the distance dispersed, however, the invasion dynamics are strongly affected by the strength of the consumer-resource interaction, and population cycles behind the wave front lead to fluctuating rates of spread. Our results suggest that for actively dispersing invaders, invasion dynamics can be determined by species interactions. More practically, our work suggests that reducing invader densities behind the front may be a useful method of slowing an invader's rate of spread.

Animals↗
PubMed2006

Theoretical analysis of high-resolution digital mammography.

The performance of a high-resolution charge coupled device-based full-field digital mammography imager was analysed using a mathematical framework based on an adaptation of cascaded linear systems theory described by other investigators. This work has been conducted in order to understand the impact of various design parameters on the physical performance characteristics of the imager. Specifically, the effect of pixel size, scintillator thickness and packing density, x-ray spectra, air kerma, dark current, charge integration time, and pixel fill-factor on the frequency dependent detective quantum efficiency was studied using a charge-coupled device as a reference platform. The imaging system was modelled as a series of physical processes with gain and spatial spreading. For each stage, the signal and noise power spectra were computed and propagated through the imaging chain as inputs to subsequent stages. Good agreement between experimental and theoretical predictions was obtained for various x-ray spectral conditions that were investigated. The modulation transfer function, MTF(f) and detective quantum efficiency DQE(f) characteristics obtained in this study are encouraging and comparable to other digital mammography systems. The results of this study strongly suggest the feasibility of large area scintillator-based digital mammography imagers with pixel sizes below 100 microm.

Algorithms↗
PubMed2004

Endothelin-1 and IP3 induced Ca2+ sparks in pulmonary arterial smooth muscle cells.

Endothelin-1 has been implicated as an important modulator or mediator of acute and chronic hypoxic pulmonary hypertension. It has been shown that endothelin-1 increases [Ca2+]i and contraction in pulmonary arterial smooth muscle cells. Recently, we have identified local Ca2+ release transients or Ca2+ sparks, which represent Ca2+ release from clusters of ryanodine receptors on the sarcoplasmic reticulum, in pulmonary arterial smooth muscle cells. These pulmonary Ca2+ sparks were associated with membrane depolarization, and activated specifically by endothelin-1 via endothelin-A receptor activation of phospholipase C and inositol trisphosphate production, possibly through local Ca2+ signaling between inositol trisphosphate receptors and ryanodine receptors. To test this hypothesis, we measured Ca2+ sparks in intralobar pulmonary arterial smooth muscle cells using laser scanning microscopy, and compared the spatiotemporal properties of Ca2+ sparks activated by endothelin-1 and by photorelease of inositol trisphosphate. We found that both endothelin-1 and inositol trisphosphate had similar effects on Ca2+ sparks. They both increased spark frequency, elevated spark amplitude and prolonged duration, without any significant effect on the spatial spread or size of Ca2+ sparks. These results provide further support to the suggestion that inositol trisphosphate production stimulated by endothelin-1 can account for the activation of Ca2+ sparks in pulmonary arterial smooth muscle cells.

Animals↗
PubMed1996

Sequential appearance and accumulation of pathognomonic markers in the central nervous system of hamsters orally infected with scrapie.

Both infectivity and TSE-specific amyloid protein (also referred to as protease resistant- or prion protein, PrP) are pathognomonic markers for transmissible spongiform encephalopathies (TSE). This paper presents a new densitometric method for the quantification of TSE-specific amyloid protein and its application to studying the pathogenesis of scrapie in Syrian hamsters after infection with scrapie strain 263K. A first study established a close correlation between infectivity and TSE-specific amyloid protein with a doubling time of 2-2.6 days in the brain and cervical spinal cord for both markers. The ratio of infectivity and TSE-specific amyloid protein was relatively constant at a mean value of about 10(6) protein molecules per infectious unit during the course of infection. A subsequent study addressed the temporal-spatial spread of infection in the central nervous system by tracing the accumulation of the pathological protein. The pathogenetic process was first detected in the spinal cord between vertebrae T4 and T9, and then showed an anterograde and retrograde spread with a rate of 0.8-1.0 mm/day. There were also some indications for a possible alternative route of spread of infection from the periphery to the brain, other than via the spinal cord. Involvement of the spleen did not appear essential for the early pathogenesis in hamsters orally infected with the 263K strain of scrapie.

Administration, Oral↗
PubMed2004

Concentrations of atmospheric sulfur compounds in an extremely snowy region, the Hokuriku District, Japan.

The diurnal and seasonal characteristics in gaseous sulfur dioxide and sulfate in aerosol particles, as well as the concentrations of sulfate in rain and snow, were measured in the Hokuriku District, Japan in order to investigate the spatial spread pattern of sulfur compounds and identify the origin of sulfur. The concentration of sulfur dioxide showed a distinct diurnal pattern, while the concentrations of nss-SO4(2-) in precipitation and aerosol particles did not. These results implied that the sulfur dioxide might originate in local emissions and did not affect the concentration of nss-SO4(2-) in precipitation, while nss-SO4(2-) in aerosol particles seemed to be widespread and might result from long-range transportation. The deposition of nss-SO42- in precipitation increased in winter, while the concentration of nss-SO4(2-) in aerosol particles decreased. This could be attributed to the lower cloud base often observed in this district in winter associated with a higher washout ratio.

Aerosols↗
PubMed2003

Multisoliton propagation in a linear granular chain.

When m grains hit a linear Hertzian chain of identical grains, m solitons are generated. We studied the multisoliton propagation using a particle dynamic simulation. The speed of solitons depends not only on the number of colliding grains but also on the sequence of generation. We found the hierarchy and evolution of the solitons as well as the generation of secondary solitons. We also found the oscillation and beats in the kinetic energy of the chain, which come from the discreteness of the medium in comparison with the spatial spreading of the soliton.

Journal Article↗
PubMed2002

Nanoscale imaging of electronic surface transport probed by atom movements induced by scanning tunneling microscope current.

The hopping movements of Cl atoms on a Si(111)-(7 x 7) surface that are enhanced by an electron injection from tips of a scanning tunneling microscope (STM) exhibit a spatial spread from the electron injection point with an anisotropic distribution. The enhanced hopping effect becomes greatest at a sample bias voltage being resonant with the Si-Cl antibonding states and also exhibits an oscillatory decay with the distance from the injection point characterized by the wavelength depending on the bias voltage. All of these facts can be interpreted in terms of the coherent expansion of the electron wave packets locally formed at the STM tip.

Journal Article↗
PubMed1998

A continuum of InsP3-mediated elementary Ca2+ signalling events in Xenopus oocytes.

1. The elementary release events underlying inositol 1,4, 5-trisphosphate (InsP3)-mediated calcium signalling were investigated in Xenopus oocytes by means of high-resolution confocal linescan imaging together with flash photolysis of caged InsP3. 2. Weak photolysis flashes evoked localized, transient calcium signals that arose at specific sites following random latencies of up to several seconds. The duration, spatial spread and amplitude of these elementary events varied widely. Event durations (at half-maximal amplitude) were distributed exponentially between about 100 and 600 ms. Fluorescence magnitudes (F/F0 of Oregon Green 488 BAPTA-1) showed a skewed distribution with a peak at about 1.5 and a tail extending as high as 3.5. 3. Individual release sites exhibited both small events (blips) and large events (puffs). The spatiotemporal distribution of calcium signals during puffs was consistent with calcium diffusion from a point source (< a few hundred nanometres), rather than with propagation of a microscopic calcium wave. 4. Estimates of the calcium flux associated with individual events were made by integrating fluorescence profiles along the scan line in three dimensions to derive the 'signal mass' at each time point. The smallest resolved events corresponded to liberation of < 2 x 10-20 mol Ca2+, and large events to about 2 x 10-18 mol Ca2+. The rise of signal mass was more prolonged than that of the fluorescence intensity, suggesting that calcium liberation persists even while the fluorescence begins to decline. Rates of rise of signal mass corresponded to Ca2+ currents of 0.4-2.5 pA. 5. Measurements of signal mass from different events showed a continuous, exponential distribution, arising through variability in magnitude and duration of calcium flux. 6. We conclude that localized calcium transients in the oocyte represent a continuum of events involving widely varying amounts of calcium liberation, rather than falling into separate populations of 'fundamental' and 'elementary' events (blips and puffs) involving, respectively, single and multiple InsP3 receptor channels. This variability probably arises through stochastic variation in both the number of channels recruited and the duration of channel opening.

Animals↗
PubMed1999

Focal agonist stimulation results in spatially restricted Ca2+ release and capacitative Ca2+ entry in bovine vascular endothelial cells.

1. Intracellular Ca2+ ([Ca2+]i) signals were studied with spatial resolution in bovine vascular endothelial cells using the fluorescent Ca2+ indicator fluo-3 and confocal laser scanning microscopy. Single cells were stimulated with the purinergic receptor agonist ATP resulting in an increase of [Ca2+]i due to intracellular Ca2+ release from inositol 1,4,5-trisphosphate (IP3)-sensitive stores. ATP-induced Ca2+ release was quantal, i.e. submaximal concentrations mobilized only a fraction of the intracellularly stored Ca2+. 2. Focal receptor stimulation in Ca2+-free solution by pressure application of agonist-containing solution through a fine glass micropipette resulted in a spatially restricted increase in [Ca2+]i. Ca2+ release was initiated at the site of stimulation and frequently propagated some tens of micrometres into non-stimulated regions. 3. Local Ca2+ release caused activation of capacitative Ca2+ entry (CCE). CCE was initially colocalized with Ca2+ release. Following repetitive focal stimulation, however, CCE became detectable at remote sites where no Ca2+ release had been observed. In addition, the rate of Ca2+ store depletion with repetitive local activation of release in Ca2+-free solution was markedly slower than that elicited by ATP stimulation of the entire cell. 4. From these experiments it is concluded that both intracellular IP3-dependent Ca2+ release and activation of CCE are controlled locally at the subcellular level. Moreover, redistribution of intracellular Ca2+ stored within the endoplasmic reticulum efficiently counteracts local store depletion and accounts for the spatial spread of CCE activation.

Action Potentials↗
PubMed2001

Predetermined recruitment of calcium release sites underlies excitation-contraction coupling in rat atrial myocytes.

Excitation-contraction coupling (E-C coupling) was studied in isolated fluo-3-loaded rat atrial myocytes at 22 and 37 degrees C using rapid confocal microscopy. Within a few milliseconds of electrical excitation, spatially discrete subsarcolemmal Ca2+ signals were initiated. Twenty to forty milliseconds after stimulation the spatial overlap of these Ca2+ signals gave a 'ring' of elevated Ca2+ around the periphery of the cells. However, this ring was not continuous and substantial Ca2+ gradients were observed. The discrete subsarcolemmal Ca2+-release sites, which responded in a reproducible sequence to repetitive depolarisations and displayed the highest frequencies of spontaneous Ca2+ sparks in resting cells, were denoted 'eager sites'. Immunostaining atrial myocytes for type II ryanodine receptors (RyRs) revealed both subsarcolemmal 'junctional' RyRs, and also 'non-junctional' RyRs in the central bulk of the cells. A subset of the junctional RyRs comprises the eager sites. For cells paced in the presence of 1 mM extracellular Ca2+, the response was largely restricted to a subsarcolemmal 'ring', while the central bulk of the cell displayed a approximately 5-fold lower Ca2+ signal. Under these conditions the non-junctional RyRs were only weakly activated during E-C coupling. However, these channels are functional and the Ca2+ stores were at least partially loaded, since substantial homogeneous Ca2+ signals could be stimulated in the central regions of atrial myocytes by application of 2.5 mM caffeine. Neither the location nor activation order of the eager sites was affected by increasing the trigger Ca2+ current (by increasing extracellular Ca2+ to 10 mM) or the sarcoplasmic reticulum (SR) Ca2+ load (following 1 min incubation in 10 mM extracellular Ca2+), although with increased SR Ca2+ load, but not greater Ca2+ influx, the delay between the sequential activation of eager sites was reduced. In addition, increasing the trigger Ca2+ current or the SR Ca2+ load changed the spatial pattern of the Ca2+ response, in that the Ca2+ signal propagated more reliably from the subsarcolemmal initiation sites into the centre of the cell. Due to the greater spatial spread of the Ca2+ signals, the averaged global Ca2+ transients increased by approximately 500 %. We conclude that rat atrial myocytes display a predetermined spatiotemporal pattern of Ca2+ signalling during early E-C coupling. A consistent set of eager Ca2+ release sites with a fixed location and activation order on the junctional SR serve to initiate the cellular response. The short latency for activation of these eager sites suggests that they reflect clusters of RyRs closely coupled to voltage-operated Ca2+ channels in the sarcolemma. Furthermore, their propensity to show spontaneous Ca2+ sparks is consistent with an intrinsically higher sensitivity to Ca2+-induced Ca2+ release. While the subsarcolemmal Ca2+ response can be considered as stereotypic, the central bulk of the cell grades its response in direct proportion to cellular Ca2+ load and Ca2+ influx.

Animals↗
PubMed2002

Crosstalk between ryanodine receptors and IP(3) receptors as a factor shaping spontaneous Ca(2+)-release events in rabbit portal vein myocytes.

In smooth muscle cells freshly isolated from rabbit portal vein, there was only one site discharging the majority of spontaneous Ca(2+)-release events; the activity of this single site was studied using laser scanning confocal imaging after loading the cells with the fluorescent Ca(2+) indicator fluo-4 acetoxymethyl ester. Localised spontaneous Ca(2+)-release events visualised by line-scan imaging revealed two predominant spatiotemporal patterns: (i) small-amplitude, fast events similar to Ca(2+) sparks in cardiomyocytes and (ii) larger and slower events. The sum of two Gaussian profiles was well fitted to the amplitude histogram (peak frequencies at 1.8 and 3.2 F/F(0)) and spatial spread (full width at half-maximal amplitude) histogram (peak frequencies at 2 and 3.8 microm) for the 230 localised Ca(2+)-release events analysed. The existence of two populations of Ca(2+)-release events was also supported by the histograms of the rise times and half-decay times, which revealed modes at 38 and 65 ms, respectively. Shifting the scan line along the z-axis during imaging from a single discharge site suggested that the appearance of two populations of Ca(2+)-release events is not due to out-of-focus imaging. Both small and large events persisted upon 3-5 min exposure to 1-5 microM nicardipine, but were abolished after 10-15 min exposure to 50-100 microM ryanodine, 0.1 microM thapsigargin or 10 microM cyclopiazonic acid. Only small-amplitude, fast events persisted in the presence of inhibitors of inositol 1,4,5-trisphosphate (IP(3))-induced Ca(2+) release, 10 microM xestospongin C or 30 microM 2-aminoethoxy-diphenylborate (2-APB), or in the presence of 2.5 microM U-73122 (a phospholipase C (PLC) inhibitor). Coupling between neighbouring Ca(2+)-release domains giving rise to spontaneous [Ca(2+)](i) waves was abolished in the presence of 2-APB. Examination of the saltatory propagation of the waves suggested that the critical factor that determines propagation between domains is a time-dependent change in the sensitivity of ryanodine receptors and/or IP(3) receptors to Ca(2+), which can give rise to 'loose coupling' between release sites. These results suggest that activation of IP(3) receptors (due to the tonic activity of PLC and ongoing production of IP(3)) recruits neighbouring domains of ryanodine receptors, leading to larger Ca(2+) releases and saltatory propagation of [Ca(2+)](i) waves in portal vein myocytes.

Animals↗
PubMed2004

Mitochondrial modulation of Ca2+ sparks and transient KCa currents in smooth muscle cells of rat cerebral arteries.

Mitochondria sequester and release calcium (Ca(2+)) and regulate intracellular Ca(2+) concentration ([Ca(2+)](i)) in eukaryotic cells. However, the regulation of different Ca(2+) signalling modalities by mitochondria in smooth muscle cells is poorly understood. Here, we investigated the regulation of Ca(2+) sparks, Ca(2+) waves and global [Ca(2+)](i) by mitochondria in cerebral artery smooth muscle cells. CCCP (a protonophore; 1 microm) and rotenone (an electron transport chain complex I inhibitor; 10 microm) depolarized mitochondria, reduced Ca(2+) spark and wave frequency, and elevated global [Ca(2+)](i) in smooth muscle cells of intact arteries. In voltage-clamped (-40 mV) cells, mitochondrial depolarization elevated global [Ca(2+)](i), reduced Ca(2+) spark amplitude, spatial spread and the effective coupling of sparks to large-conductance Ca(2+)-activated potassium (K(Ca)) channels, and decreased transient K(Ca) current frequency and amplitude. Inhibition of Ca(2+) sparks and transient K(Ca) currents by mitochondrial depolarization could not be explained by a decrease in intracellular ATP or a reduction in sarcoplasmic reticulum Ca(2+) load, and occurred in the presence of diltiazem, a voltage-dependent Ca(2+) channel blocker. Ru360 (10 microm), a mitochondrial Ca(2+) uptake blocker, and lonidamine (100 microm), a permeability transition pore (PTP) opener, inhibited transient K(Ca) currents similarly to mitochondrial depolarization. In contrast, CGP37157 (10 microm), a mitochondrial Na(+)-Ca(2+) exchange blocker, activated these events. The PTP blockers bongkrekic acid and cyclosporin A both reduced inhibition of transient K(Ca) currents by mitochondrial depolarization. These results indicate that mitochondrial depolarization leads to a voltage-independent elevation in global [Ca(2+)](i) and Ca(2+) spark and transient K(Ca) current inhibition. Data also suggest that mitochondrial depolarization inhibits Ca(2+) sparks and transient K(Ca) currents via PTP opening and a decrease in intramitochondrial [Ca(2+)].

Animals↗
PubMed2005

Elementary purinergic Ca2+ transients evoked by nerve stimulation in rat urinary bladder smooth muscle.

The translation of nerve transmission to Ca2+ signals in urinary bladder smooth muscle (UBSM) is incompletely understood. Thus, we sought to characterize Ca2+ signals in strips of UBSM loaded with the Ca2+-sensitive fluorescent dye, fluo-4, using laser scanning confocal microscopy. Two types of Ca2+ signals occurred spontaneously and could be evoked with field stimulation: large, rapid, global Ca2+ transients termed 'global Ca2+ flashes', and much smaller, localized Ca2+ transients. Global Ca2+ flashes were inhibited by the L-type voltage-dependent Ca2+ channel (VDCC) inhibitor, diltiazem and with P2X receptor blockade. Simultaneous intracellular recordings and Ca2+ measurements indicated that these events are caused by Ca2+ influx through VDCCs during action potentials. Small, local Ca2+ transients occurred spontaneously, and their frequency could be elevated with field stimulation. Atropine, an inhibitor of muscarinic receptors, did not affect these local Ca2+ transients. However, the desensitizing P2X receptor agonist alpha,beta-methylene ATP, and the purinergic antagonist, suramin, effectively inhibited the local Ca2+ transients. The frequency of these 'purinergic Ca2+ transients' was increased about 7-fold by a 10 s stimulus train (1 Hz). The amplitude, duration at one-half amplitude and the spatial spread of the evoked purinergic Ca2+ transients were F/F(o) = 2.4 +/- 0.13, 111.7 +/- 9.3 ms and 14.0 +/- 1.0 microm2, respectively. Tetrodotoxin inhibited evoked purinergic Ca2+ transients, indicating that they were dependent on nerve fibre activation. Purinergic Ca2+ transients were not dependent on VDCC activity. Neither 2-APB, an inhibitor of inositol 1,4,5-triphosphate (Ins(1,4,5)P3) (IP3)-induced Ca2+ release, nor ryanodine inhibited the purinergic Ca2+ transients. We have identified two novel Ca2+ signals in rat UBSM. Large, rapid, global Ca2+ flashes that represent Ca2+ influx through VDCCs during action potentials, and local, purinergic Ca2+ transients that represent Ca2+ entry through P2X receptors. Our results indicate that purinergic Ca2+ transients evoked by release of ATP from nerve varicosities are elementary signals in the process of nerve-smooth muscle communication.

Animals↗