Sarcoplasmic Reticulum Function in Smooth Muscle

Abstract

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 contribution of the elemental Ca signals from the SR, sparks and puffs, to global Ca signals, i.e., Ca waves and oscillations, is becoming clearer but is far from established. The dynamics of SR Ca release and uptake mechanisms are reviewed along with the control of luminal Ca. We review the growing list of the SR's functions that still includes Ca storage, contraction, and relaxation but has been expanded to encompass Ca homeostasis, generating local and global Ca signals, and contributing to cellular microdomains and signaling in other organelles, including mitochondria, lysosomes, and the nucleus. For an integrated approach, a review of aspects of the SR in health and disease and during development and aging are also included. While the sheer versatility of smooth muscle makes it foolish to have a “one model fits all” approach to this subject, we have tried to synthesize conclusions wherever possible.

Ca2+ entry following P2X receptor activation induces IP3 receptor‐mediated Ca2+ release in myocytes from small renal arteries

“…Indeed, the results of early experiments conducted on permeabilized strips of portal vein, pulmonary artery and taenia caeci suggested the existence of two separate calcium stores: Sa expressing both RyRs and IP3Rs and Sb expressing only IP3Rs. The contribution of the Sb store to IP3-induced Ca 2+ release was estimated to be 60% in taenia caecum, 40% in pulmonary artery and only 6% in portal vein (reviewed in Wray and Burdyga, 2010). In contrast, the results of more recent experiments conducted on isolated pulmonary artery myocytes suggested that IP3-releasable and caffeine-releasable calcium stores are virtually completely separate (Janiak et al, 2001).…”

“…Either of these events, which cause an initial rise in [Ca 2+ ]i, may be further augmented by ryanodine receptor (RyR)-mediated Ca 2+ release activated via a Ca 2+ -induced Ca 2+ release (CICR) mechanism (Fabiato and Fabiato, 1975). However, the recruitment of RyR-mediated Ca 2+ release by voltage-gated Ca 2+ entry and/or IP3R-mediated Ca 2+ release in smooth muscles is still an area of extensive debate and controversy (reviewed in Laporte et al, 2004;Wray and Burdyga, 2010). Indeed, the relative contribution of RyRs and IP3Rs to intracellular [Ca 2+ ]i mobilization varies in different types of SMCs, and often depends on the strengths and mechanism of SMC stimulation.…”

“…An increase in [Ca 2+ ]i in smooth muscle cell (SMC) is caused by either depolarization of the myocyte membrane (electromechanical coupling; Somlyo and Somlyo, 1968) resulting from activation of ionotropic receptors or metabotropic receptor-coupled cationic channels and leading to Ca 2+ influx via voltage-gated Ca 2+ channels (VGCCs), or by activation of metabotropic receptors (pharmacomechanical coupling; Somlyo and Somlyo, 1968) coupled via Gq/11-protein to phospholipase C (PLC) activation followed by inositol 1,4,5-trisphosphate (IP3) liberation and IP3 receptor (IP3R)-mediated Ca 2+ release, or by a combination of these mechanisms Davis and Hill, 1999;Wray and Burdyga, 2010). Either of these events, which cause an initial rise in [Ca 2+ ]i, may be further augmented by ryanodine receptor (RyR)-mediated Ca 2+ release activated via a Ca 2+ -induced Ca 2+ release (CICR) mechanism (Fabiato and Fabiato, 1975).…”

“…However, other research groups working on different or even the same SMC type failed to detect any evidence of CICR (Fleischmann et al, 1996;Kamishima and McCarron, 1996;Bradley et al, 2002). The ability of Ca 2+ liberated via IP3Rs to trigger RyR-mediated Ca 2+ release also varies among different types of smooth muscles and depends on receptor distribution and isoform expression (reviewed in Wray and Burdyga, 2010). Emerging evidence highlights the importance of RyRs and CICR in calcium signalling and arteriolar contraction in the renal microcirculation.…”

“…However, other research groups working on different or even the same SMC type failed to detect any evidence of CICR (Fleischmann et al, 1996;Kamishima and McCarron, 1996;Bradley et al, 2002). The ability of Ca 2+ liberated via IP3Rs to trigger RyR-mediated Ca 2+ release also varies among different types of smooth muscles and depends on receptor distribution and isoform expression (reviewed in Wray and Burdyga, 2010 Two major sympathetic cotransmitters, noradrenaline and ATP, mediate vasoconstriction of small arteries (Wier et al, 2009) by acting on metabotropic a1-adrenoceptors and ionotropic P2X receptors respectively. Thus, P2X receptors provide an important therapeutic target, mediating substantial vasoconstrictor drive resistant to adrenoceptor antagonists (Wier et al, 2009).…”