From contraction to gene expression: nanojunctions of the sarco/endoplasmic reticulum deliver site- and function-specific calcium signals

SCIENCE CHINA Life Sciences SPECIAL TOPIC: Ca2+ • REVIEW • doi: 10.1007/s11427-016-5071-0 doi: 10.1007/s11427-016-5071-0 From contraction to gene expression: nanojunctions of the sarco/endoplasmic reticulum deliver site- and function-specific calcium signals A. Mark Evans1*, Nicola Fameli2, Oluseye A. Ogunbayo1, Jingxian Duan1 & Jorge Navarro-Dorado1 1 Centre for Integrative Physiology, College of Medicine and Veterinary Medicine, Hugh Robson Building, University of Edinburgh, Edinburgh EH8 9XD, UK; 2 Institute of Biophysics, Medical University of Graz, Graz, Austria Received March 5, 2015; accepted April 7, 2016 Calcium signals determine, for example, smooth muscle contraction and changes in gene expression. How calcium signals select for these processes is enigmatic. We build on the “panjunctional sarcoplasmic reticulum” hypothesis, describing our view that different calcium pumps and release channels, with different kinetics and affinities for calcium, are strategically positioned within nanojunctions of the SR and help demarcate their respective cytoplasmic nanodomains. SERCA2b and RyR1 are preferentially targeted to the sarcoplasmic reticulum (SR) proximal to the plasma membrane (PM), i.e., to the superficial buffer barrier formed by PM-SR nanojunctions, and support vasodilation. In marked contrast, SERCA2a may be entirely restricted to the deep, perinuclear SR and may supply calcium to this sub-compartment in support of vasoconstriction. RyR3 is also preferentially targeted to the perinuclear SR, where its clusters associate with lysosome-SR nanojunctions. The distribution of RyR2 is more widespread and extends from this region to the wider cell. Therefore, perinuclear RyR3s most likely support the initiation of global calcium waves at L-SR junctions, which subsequently propagate by calcium-induced calcium release via RyR2 in order to elicit contraction. Data also suggest that unique SERCA and RyR are preferentially targeted to invaginations of the nuclear membrane. Site- and function-specific calcium signals may thus arise to modulate stimulus-response coupling and transcriptional cascades. calcium, nanojunction, ryanodine receptor, sarco/endoplasmic reticulum calcium ATPase, smooth muscle, gene expression, contraction Citation: Evans, A.M., Fameli, N., Ogunbayo, O.A., Duan, J., and Jorge, N.D. (2016). From contraction to gene expression: nanojunctions of the sarco/endoplasmic reticulum deliver site- and function-specific calcium signals. Sci China Life Sc. doi: 10.1007/s11427-016-5071-0 INTRODUCTION Ca2+ signals govern a wide variety of cell functions, from muscle contraction, exocytosis and cell division to gene expression. Cells must therefore provide for the generation of different Ca2+ signals that select for one or a combination of functions. Given the multiplicity of functional signals we must therefore ask: how can fluctuations in the concentraemail: tion of one ion, Ca2+, exert such selective and multifaceted control? The generally accepted view is that both the spatial and temporal characteristics of Ca2+ transients code for selective modulation of molecular targets and thereby engage appropriate cell and system function. In all cell types stimulus-response coupling is largely controlled by interactions between voltage-gated Ca2+ channels of the plasma membrane (PM) or its invaginations (T-tubules or caveolae) and Ca2+ release channels in the sarco/endoplasmic reticulum (S/ER). Pharmaco-response © The Author(s) 2016. This article is published with open access at link.springer.com life.scichina.com link.springer.com 2 Evans, A.M., et al. Sci China Life Sci coupling provides for greater signal diversity, via gating of the 3 known S/ER resident IP3 receptors (IP3R1-3) by inositol 1,4,5 trisphosphate (IP3) (Berridge, 2008), modulation of the 3 S/ER resident ryanodine receptors subtypes (RyR1-3) by Ca2+ and/or cyclic adenosine diphosphateribose (cADPR) (Evans et al., 2005b; Lee, 2004; Morgan and Galione, 2008), and by the gating of the endolysosome targeted two pore channels (TPC1-3). Clearly, therefore, the spatiotemporal pattern of Ca2+ signals will be governed by those Ca2+ mobilising messenger(s) recruited by a given stimulus, the Ca2+ release channels expressed by a given cell and the consequential selection by these messengers of Ca2+ release from designate intracellular Ca2+ stores (Churchill et al., 2002; Kinnear et al., 2004; Yamasaki et al., 2004). However, while there is a degree of flexibility within the identified signalling pathways described thus far, the current model still appears to be too simplistic to allow for the appropriate governance of all known Ca2+-dependent processes from, for example, gene expression, autophagy and cell proliferation to contraction and programmed cell death. The present article will focus on the growing body of evidence in support of the view that the functional specification of Ca2+ signals is determined by the targeting of Ca2+ release channels and transporters to junctional complexes formed by membrane-membrane pairs that are less than 30nm apart in all relevant cases reported to date. The specified distance of separation alone designates these complexes as nanojunctions (NOT MICRODOMAINS!) which have now been shown to exist between the S/ER and the plasma membrane (PM), lysosomes, mitochondria and the nucleus (van Breemen et al., 2013). The underlying mechanisms of signal generation are likely more elaborate in nature and clearly rely on the strategic spatial positioning within each nanojunction of different types of Ca2+ transporters and release channels, each of which may be characterized by different kinetics and affinities for Ca2+ (Clark et al., 2010). WHAT ARE NANOJUNCTIONS? Perhaps the first nanojunction ever described in terms of its functional importance was an intercellular junction, namely the neuromuscular junction. Here the pre- and postjunctional membranes are approximately 20 nm apart and extend roughly parallel to each other for several hundred nm. There is no doubt as to the importance of this nanojunction to our understanding of how the release of acetylcholine coordinates neuromuscular transmission (Del Castillo and Katz, 1956). By comparison, however, little attention has been given to the presence, function and plasticity of nanojunctions between intracellular membranes. Perhaps the one exception is in skeletal and cardiac muscles, where the importance to excitation-contraction coupling of the junctional complexes formed between the T-tubules of the sarcolemma and terminal cisternae of the sarcoplasmic reticulum is well July (2016) Vol.59 No.7 documented. Importantly, in each instance the junctional membrane pair are separated by ~20nm or less (Franzini-Armstrong, 1964; Ramesh et al., 1998; Rosenbluth, 1962), akin to the neuromuscular junction. In cardiac muscle, sarcolemma-SR nanojunctions are essential to the targeting of Ca2+ influx to those RyRs located on the ter (...truncated)