Suppression Of Calcium Release Research Articles

Calcitonin and Bone Physiology: In Vitro, In Vivo, and Clinical Investigations.

Calcitonin was discovered as a peptide hormone that was known to reduce the calcium levels in the systemic circulation. This hypocalcemic effect is produced due to multiple reasons such as inhibition of bone resorption or suppression of calcium release from the bone. Thus, calcitonin was said as a primary regulator of the bone resorption process. This is the reason why calcitonin has been used widely in clinics for the treatment of bone disorders such as osteoporosis, hypercalcemia, and Paget's disease. However, presently calcitonin usage is declined due to the development of efficacious formulations of new drugs. Calcitonin gene-related peptides and several other peptides such as intermedin, amylin, and adrenomedullin (ADM) are categorized in calcitonin family. These peptides are known for the structural similarity with calcitonin. Aside from having a similar structure, these peptides have few overlapping biological activities and signal transduction action through related receptors. However, several other activities are also present that are peptide specific. In vitro and in vivo studies documented the posttreatment effects of calcitonin peptides, i.e., positive effect on bone osteoblasts and their formation and negative effect on osteoclasts and their resorption. The recent research studies carried out on genetically modified mice showed the inhibition of osteoclast activity by amylin, while astonishingly calcitonin plays its role by suppressing osteoblast and bone turnover. This article describes the review of the bone, the activity of the calcitonin family of peptides, and the link between them.

Suppression of Calcium Release from Inositol 1,4,5-Trisphosphate-sensitive Stores Mediates the Anti-apoptotic Function of Nuclear Factor-κB

The activation of the transcription factor nuclear factor-kappaB (NF-kappaB) by growth factors, cytokines, and cellular stress can prevent apoptosis, but the underlying mechanism is unknown. Here we provide evidence for an action of NF-kappaB on calcium signaling that accounts for its anti-apoptotic function. Embryonic fibroblasts lacking the transactivating subunit of NF-kappaB RelA (p65) exhibit enhanced inositol 1,4,5-trisphosphate (IP(3)) receptor-mediated calcium release and increased sensitivity to apoptosis, which are restored upon re-expression of RelA. The size of the endoplasmic reticulum (ER) calcium pool and the number of IP(3) receptors per cell are decreased in response to stimuli that activate NF-kappaB and are increased when NF-kappaB activity is suppressed. The selective antagonism of IP(3) receptors blocks apoptosis in RelA-deficient cells, whereas activation of NF-kappaB in normal cells leads to decreased levels of the type 1 IP(3) receptor and decreased calcium release. Overexpression of Bcl-2 normalizes ER calcium homeostasis and prevents calcium-mediated apoptosis in RelA-deficient cells. These findings establish an ER calcium channel as a pivotal target for NF-kappaB-mediated cell survival signaling.

Association of the Iγ and Iδ Charge Movement with Calcium Release in Frog Skeletal Muscle

Charge movement and calcium transient were measured simultaneously in stretched frog cut twitch fibers under voltage clamp, with the internal solution containing 20mM EGTA plus added calcium and antipyrylazo III. When the nominal free [Ca2+]i was 10nM, the shape of the broad Iγ hump in the ON segments of charge movement traces remained invariant when the calcium release rate was greatly diminished. When the nominal free [Ca2+]i was 50nM, which was close to the physiological level, the Iγ humps were accelerated and a slow calcium-dependent Iδ component (or state) was generated. The peak of ON Iδ synchronized perfectly with the peak of the calcium release rate whereas the slow decay of ON Iδ followed the same time course as the decay of calcium release rate. Suppression of calcium release by TMB-8 reduced the amount of Qδ concomitantly but not completely, and the effects were partially reversible. The same simultaneous suppression effects were achieved by depleting the sarcoplasmic reticulum calcium store with repetitive stimulation. The results suggest that the mobility of Qδ needs to be primed by a physiological level of resting myoplasmic Ca2+. Once the priming is completed, more Iδ is mobilized by the released Ca2+ during depolarization.

Suppression of calcium release by calcium or procaine in voltage clamped rat skeletal muscle fibres.

1. Calcium transients were measured in fast-twitch rat skeletal muscle fibres stretched to 3.7-4.0 microns per sarcomere, and voltage clamped at a holding potential of -80 mV using the double-seal Vaseline gap technique. Resting calcium was monitored with fura-2 and the calcium transients were measured with antipyrylazo III. The rate of release of calcium from the sarcoplasmic reticulum was calculated from the calcium transient records. The temperature was 14-17 degrees C. 2. The steady-state calcium dependence of inactivation of release was studied with a two-pulse protocol in which 200 ms prepulses of different amplitudes elevated the internal calcium concentration to various levels. The inactivation of release was then measured in the test pulse that followed the prepulses. The calcium concentration at which the inactivation of release are half-maximal was approximately 0.22 microM, the average number of bound calcium ions needed to cause inactivation was about three per release channel and the amount of release that could be inactivated was, on average, 2.48 times the steady level of release during the test pulses. 3. Procaine (0.3mM) reversibly decreased the amplitude and the rate of rise of the calcium transient. Both the peak and the steady level of release were decreased by about 50%. The shape of the release waveform was not modified.

The acute hypocalcaemic effect of ethanol and its mechanism of action in the rat

The hypocalcaemic action of ethanol (3 g/kg body weight) was investigated in intact, thyroparathyroidectomized and antrectomized rats. It was found that ethanol administered either intraperitoneally or orally reduced plasma calcium concentrations within 30 min and that this response lasted for 8 h. Additional studies performed in antrectomized and thyroparathyroidectomized rats indicated that neither gastrin nor the hormones parathormone and calcitonin had any effect on the hypocalcaemic effect of ethanol. Investigation of the mechanism of action of ethanol-induced hypocalcaemia involved measurements of calcium efflux from and influx into the plasma pool. Ethanol did not have any effect on the disappearance from plasma of 45Ca administered intravenously at 0 min. In contrast, ethanol was found to enhance the disappearance of 45Ca administered intraperitoneally 17 h prior to the experiment. The interpretation of 45Ca studies was discussed and it was concluded that ethanol-induced hypocalcaemia resulted from a decrease in calcium influx into the plasma. Additional in vitro studies did not indicate the suppressive action of ethanol on the release of calcium from tibias. In conclusion, our results show that the mechanism of hypocalcaemia caused by ethanol is the suppression of calcium release from some tissue(s) into the plasma.