Laporte R, Hui A, Laher I: Pharmacological modulation of sarcoplasmic reticulum function in smooth muscle (original) (raw)
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Regulation of the rat sarcoplasmic reticulum calcium release channel by calcium
2000
The regulation by calcium of the ryanodine receptor/SR calcium release channel (RyR) from rat skeletal muscle was studied under isolated conditions and in situ. RyRs were either solubilized and incorporated into lipid bilayers or single fibres were mounted into a Vaseline gap voltage clamp. Single channel data were compared to parameters determined from the calculated calcium release flux. With K+ (250 mM) being the charge carrier the single channel conductance was 529 pS at 50 microM Ca2+ cis and trans, and decreased with increasing cis [Ca2+]. Open probability showed a bell shaped calcium dependence revealing an activatory and an inhibitory Ca2+ binding site (Hill coefficients of 1.18 and 1.28, respectively) with half activatory and inhibitory concentrations of 9.4 and 298 microM. The parameters of the inhibitory site agreed with the calcium dependence of channel inactivation deduced from the decline in SR calcium release in isolated fibres. Mean open time showed slight [Ca2+] dependence following a single exponential at every Ca2+ concentration tested. Closed time histograms, at high [Ca2+], were fitted with three exponentials, from which the longest was calcium independent, and resembled the recovery time constant of SR inactivation (115+/-15 ms) obtained in isolated fibres. The data are in agreement with a model where calcium binding to the inhibitory site on RyR would be responsible for the calcium dependent inactivation in situ.
Sarcoplasmic Reticulum Function in Smooth Muscle
Physiological Reviews, 2010
The sarcoplasmic reticulum (SR) of smooth muscles presents many intriguing facets and questions concerning its roles, especially as these change with development, disease, and modulation of physiological activity. The SR's function was originally perceived to be synthetic and then that of a Ca store for the contractile proteins, acting as a Ca amplification mechanism as it does in striated muscles. Gradually, as investigators have struggled to find a convincing role for Ca-induced Ca release in many smooth muscles, a role in controlling excitability has emerged. This is the Ca spark/spontaneous transient outward current coupling mechanism which reduces excitability and limits contraction. Release of SR Ca occurs in response to inositol 1,4,5-trisphosphate, Ca, and nicotinic acid adenine dinucleotide phosphate, and depletion of SR Ca can initiate Ca entry, the mechanism of which is being investigated but seems to involve Stim and Orai as found in nonexcitable cells. The contribut...
Calcium signalling in smooth muscle
Cell Calcium, 2005
Calcium signalling in smooth muscles is complex, but our understanding of it has increased markedly in recent years. Thus, progress has been made in relating global Ca 2+ signals to changes in force in smooth muscles and understanding the biochemical and molecular mechanisms involved in Ca 2+ sensitization, i.e. altering the relation between Ca 2+ and force. Attention is now focussed more on the role of the internal Ca 2+ store, the sarcoplasmic reticulum (SR), global Ca 2+ signals and control of excitability. Modern imaging techniques have shown the elaborate SR network in smooth muscles, along with the expression of IP 3 and ryanodine receptors. The role and cross-talk between these two Ca 2+ release mechanisms, as well as possible compartmentalization of the SR Ca 2+ store are discussed. The close proximity between SR and surface membrane has long been known but the details of this special region to Ca 2+ signalling and the role of local sub-membrane Ca 2+ concentrations and membrane microdomains are only now emerging. The activation of K + and Cl − channels by local Ca 2+ signals, can have profound effects on excitability and hence contraction. We examine the evidence for both Ca 2+ sparks and puffs in controlling ion channel activity, as well as a fundamental role for Ca 2+ sparks in governing the period of inexcitability in smooth muscle, i.e. the refractory period. Finally, the relation between different Ca 2+ signals, e.g. sparks, waves and transients, to smooth muscle activity in health and disease is becoming clearer and will be discussed.
The Journal of Physiology, 2006
In skeletal muscle, sarcoplasmic reticulum (SR) Ca 2+ depletion is suspected to trigger a calcium entry across the plasma membrane and recent studies also suggest that the opening of channels spontaneously active at rest and possibly involved in Duchenne dystrophy may be regulated by SR Ca 2+ depletion. Here we simultaneously used the cell-attached and whole-cell voltage-clamp techniques as well as intracellular Ca 2+ measurements on single isolated mouse skeletal muscle fibres to unravel any possible change in membrane conductance that would depend upon SR Ca 2+ release and/or SR Ca 2+ depletion. Delayed rectifier K + single channel activity was routinely detected during whole-cell depolarizing pulses. In addition the activity of channels carrying unitary inward currents of ∼1.5 pA at −80 mV was detected in 17 out of 127 and in 21 out of 59 patches in control and mdx dystrophic fibres, respectively. In both populations of fibres, large whole-cell depolarizing pulses did not reproducibly increase this channel activity. This was also true when, repeated application of the whole-cell pulses led to exhaustion of the Ca 2+ transient. SR Ca 2+ depletion produced by the SR Ca 2+ pump inhibitor cyclopiazonic acid (CPA) also failed to induce any increase in the resting whole-cell conductance and in the inward single channel activity. Overall results indicate that voltage-activated SR Ca 2+ release and/or SR Ca 2+ depletion are not sufficient to activate the opening of channels carrying inward currents at negative voltages and challenge the physiological relevance of a store-operated membrane conductance in adult skeletal muscle.
Calcium transporters and signalling in smooth muscles
Cell Calcium, 2007
Two P-type Ca transporters, the plasma membrane Ca-ATPase (PMCA) and the sarcoplasmic reticulum (SR) Ca-ATPase (SERCA), play a crucial role in maintaining Ca homeostasis, controlling contractility and contributing to excitably and cell signalling in smooth muscle cells. There is considerable structural homology between the two Ca-ATPases; they both have transmembrane spanning regions, have similar ATP-phosphorylated intermediaries, counter transport protons and are regulated by several second messengers. They both also exist in several isoforms and have many splice variants, which presumably impart some of their tissue specific functions. We describe the relative contribution of PMCA and the Na–Ca exchanger to Ca efflux in relaxation to smooth muscle, including recent data from transgenic mice, which has begun to elucidate the specific contributions of individual isoforms to Ca signalling. We then consider Ca release and uptake into the SR in smooth muscle. Experiments investigating the distribution of SERCA in smooth muscle cells have provided new insights into control of SR luminal Ca, and the effects of SR Ca load on signalling, is discussed. This is followed by a detailed consideration of the interactions between the surface membrane and SR membrane pumps, exchangers and ion channels in smooth muscle, along with their distribution to caveolae and cholesterol-rich membrane domains. Where relevant the importance of these functions to health and disease are noted. We conclude that the dynamic changes in splice variants expressed, constituents of membrane microdomains and environment of the sub-sarcolemmal space, close to the SR, need to be the focus of future research, so that the full importance of Ca transporters to smooth muscle signalling cascades can be better understood.
Superficial buffer barrier function of smooth muscle sarcoplasmic reticulum
Trends in Pharmacological Sciences, 1995
In smooth muscle the superficial sarcoplasmic reticulum accumulates a portion of the Ca2+ that enters cells through the plasmalemma and thus functions as a buffer barrier to Ca2+ entry into the myoplasm (superficial buffer barrier or SBB). In this review Cornelis van Breemen, Qian Chen and Ismail Laher summarize experimental support for the SBB, and discuss data indicating that: (1) contraction is related more to the rate than extent of Ca2+ entry; (2) refilling of sarcoplasmic reticulum from the extracellular space is mediated by Ca2+ influx and Ca2+ pumping by the sarcoplasmic reticulum Ca2+ pump; (3) the superficial sarcoplasmic reticulum unloads Ca2+ to the extracellular space by a multi step process that involves sequentially the opening of Ca2+ and inositol 1,4,5-trisphosphate [Ins(1,4,5,)P3] sensitive channels and Ca2+ extrusion by Na(+)-Ca2+ exchange; (4) the SBB generates a peripheral Ca2+ gradient; (5) Ca(2+)-mobilizing receptor agonists generate Ins(1,4,5)P3 which short circuits the SBB to increase the effectiveness of Ca2+ influx in raising [Ca2+]i and consequently increase smooth muscle contraction. A physiologically regulated SBB is thought to enhance the informational content of Ca2+ signalling and support variable reduction of smooth muscle tone. Pharmacological modulation of Ca2+ transport in the superficial sarcoplasmic reticulum therefore presents an alternative means of controlling smooth muscle tone dependent on Ca2+ entry.
Variable luminal sarcoplasmic reticulum Ca 2+ buffer capacity in smooth muscle cells
Cell Calcium, 2009
Sarcoplasmic reticulum contains the internal Ca 2+ store in smooth muscle cells and its lumen appears to be a continuum that lacks diffusion barriers. Accordingly, the free luminal Ca 2+ level is the same all throughout the SR; however, whether the Ca 2+ buffer capacity is the same in all the SR is unknown. We have estimated indirectly the luminal Ca 2+ buffer capacity of the SR by comparing the reduction in SR Ca 2+ levels with the corresponding increase in [Ca 2+ ] i during activation of either IP 3 Rs with carbachol or RyRs with caffeine, in smooth muscle cells from guinea pig urinary bladder. We have determined that carbachol-sensitive SR has a 2.4 times larger Ca 2+ buffer capacity than caffeine-sensitive SR. Rapid inhibition of SERCA pumps with thapsigargin revealed that this pump activity accounts for 80% and 60% of the Ca 2+ buffer capacities of carbachol-and caffeine-sensitive SR, respectively. Moreover, the Ca 2+ buffer capacity of carbachol-sensitive SR was similar to caffeine-sensitive SR when SERCA pumps were inhibited. Similar rates of Ca 2+ replenishments suggest similar levels of SERCA pump activities for either carbacholor caffeine-sensitive SR. Paired pulses of caffeine, in conditions of low Ca 2+ influx, indicate the relevance of luminal SR Ca 2+ buffer capacity in the [Ca 2+ ] i response. To further study the importance of luminal SR Ca 2+ buffer capacity in the release process we used low levels of heparin to partially inhibit IP 3 Rs. This condition revealed carbachol-induced transient increase of luminal SR Ca 2+ levels provided that SERCA pumps were active. It thus appears that SERCA pump activity keeps the luminal SR Ca 2+ -binding proteins in the high-capacity, low-affinity conformation, particularly for IP 3 R-mediated Ca 2+ release.
Biophysical Journal, 1996
The effects of sarcoplasmic reticulum lumenal (trans) Ca2' on cytosolic (cis) ATP-activated rabbit skeletal muscle Ca2+ release channels (ryanodine receptors) were examined using the planar lipid bilayer method. Single channels were recorded in symmetric 0.25 M KCI media with K+ as the major current carrier. With nanomolar [Ca2+] in both bilayer chambers, the addition of 2 mM cytosolic ATP greatly increased the number of short channel openings. As lumenal [Ca2`] was increased from <0.1 ,uM to-250 ,uM, increasing channel activities and events with long open time constants were seen at negative holding potentials. Channel activity remained low at positive holding potentials. Further increase in lumenal [Ca2"] to 1, 5, and 10 mM resulted in a decrease in channel activities at negative holding potentials and increased activities at positive holding potentials. A voltage-dependent activation by 50 ,uM lumenal Ca2+ was also observed when the channel was minimally activated by <1 AM cytosolic Ca2+ in the absence of ATP. With AM cytosolic Ca2+ in the presence or absence of 2 mM ATP, single-channel activities showed no or only a weak voltage dependence. Other divalent cations (Mg2+, Ba2+) could not replace lumenal Ca2+. On the contrary, cytosolic ATP-activated channel activities were decreased as lumenal Ca2' fluxes were reduced by the addition of 1-5 mM BaCI2 or MgCI2 to the lumenal side, which contained 50 ,uM Ca2+. An increase in [KCI] from 0.25 M to 1 M also reduced single-channel activities. Addition of the "fast" Ca2+ buffer 1,2-bis(2-aminophenoxy)ethanetetraacetic acid (BAPTA) to the cis chamber increased cytosolic ATP-, lumenal Ca2+-activated channel activities to a nearly maximum level. These results suggested that lumenal Ca2+ flowing through the skeletal muscle Ca2+ release channel may regulate channel activity by having access to cytosolic Ca2+ activation and Ca2+ inactivation sites that are located in "BAPTA-inaccessible" and "BAPTA-accessible" spaces, respectively.