Inhibition of SERCA pumps induces desynchronized RyR activation in overloaded internal Ca²⁺ stores in smooth muscle cells

Abstract

We have previously shown that rapid inhibition of sarcoplasmic reticulum (SR) ATPase (SERCA pumps) decreases the amplitude and rate of rise (synchronization) of caffeine induced-Ca(2+) release without producing a reduction of free luminal SR Ca(2+) level in smooth muscle cells (Gómez-Viquez L, Guerrero-Serna G, García U, Guerrero-Hernández A. Biophys J 85: 370-380, 2003). Our aim was to investigate the role of luminal SR Ca(2+) content in the communication between ryanodine receptors (RyRs) and SERCA pumps. To this end, we studied the effect of SERCA pump inhibition on RyR-mediated Ca(2+) release in smooth muscle cells with overloaded SR Ca(2+) stores. Under this condition, the amplitude of RyR-mediated Ca(2+) release was not affected but the rate of rise was still decreased. In addition, the caffeine-induced Ca(2+)-dependent K(+) outward currents revealed individual events, suggesting that SERCA pump inhibition reduces the coordinated activation of RyRs. Collectively, our results indicate that SERCA pumps facilitate the activation of RyRs by a mechanism that does not involve the regulation of SR Ca(2+) content. Importantly, SERCA pumps and RyRs colocalize in smooth muscle cells, suggesting a possible local communication between these two proteins.

Constitutive PKA activity is essential for maintaining the excitability and contractility in guinea pig urinary bladder smooth muscle: role of the BK channel

“…Caffeine at a concentration Ͼ10 mM can deplete SR Ca 2ϩ by releasing Ca 2ϩ through RyRs (11). In UBSM cells, caffeine (10 mM) transiently increased TBKCs, followed by a complete inhibition (n ϭ 9, N ϭ 6; Fig.…”

Role of Calcium in Vomiting

“…Intracellular Ca 2+ release from the sarco/endoplasmic reticulum (SER) Ca 2+ stores through the inositol triphosphate receptors (IP 3 Rs) and ryanodine receptors (RyRs) is counter-balanced by continuous Ca 2+ uptake from the cytoplasm into SER stores by the SER Ca 2+ -ATPase pump (SERCA). Thapsigargin is a specific inhibitor of SERCA and thus enhances cytosolic levels of Ca 2+ , a process involving SER Ca 2+ release via IP 3 Rs and RyRs as well as extracellular Ca 2+ entry through Ca 2+ channels located in the plasma membrane including store-operated Ca 2+ channels (SOCE) and L-type Ca 2+ channels (LTCCs) [49][50][51][52][53][54][55][56][57][58][59][60].…”

“…Role of Calcium in Vomiting http://dx.doi.org/10.5772/intechopen.78370 counter-balance the cytosolic intracellular Ca 2+ release from the sarco/endoplasmic reticulum into the cytoplasm via the inositol trisphosphate receptors (IP 3 Rs) and ryanodine receptors (RyRs) [49][50][51]. Thapsigargin also causes intracellular release of stored Ca 2+ from the sarco/ endoplasmic reticulum into the cytosol which subsequently evokes extracellular Ca 2+ influx predominantly through store-operated Ca 2+ entry (SOCE) in non-excitable cells [52][53][54].…”

Role of Calcium in Vomiting: Revelations from the Least Shrew Model of Emesis

“…[56][57][58] Intracellular Ca 2+ release from the SER into the cytoplasm is accomplished by Inositol Trisphosphate Receptors (IP 3 Rs) and Ryanodine Receptors (RyRs), and this loss is counter-balanced by continuous Ca 2+ uptake from the cytoplasm into these SER stores by SERCAs (Figure 1). …”