Mitochondria Structure and Position in the Local Control of Calcium Signals in Smooth Muscle Cells

Features of Ca2+ signals including the amplitude, duration, frequency and location are encoded by various physiological stimuli. These features of the signals are decoded by cells to selectively activate smooth muscle functions that include contraction and proliferation [1–3]. Central, therefore, to an appreciation of how smooth muscle is controlled is an understanding of the regulation of Ca2+. In smooth muscle, Ca2+ signals arise from two major sources. The first is the extracellular space from which Ca2+ enters the cell via channels such as voltage-dependent Ca2+ channels, store-operated Ca2+ (SOC) channels and various members of the transient receptor potential channel family. The second major Ca2+ source is the internal Ca2+ store (sarcoplasmic reticulum; SR) [4–6]. The SR accumulates Ca2+ using sarco/endoplasmic reticulum Ca2+-ATPases (SERCA) and Ca2+ is released from the SR via the ligand-gated channel/receptor complexes, the IP3 receptor (IP3R) and ryanodine receptor (RyR). Release of Ca2+ via IP3R is activated by IP3 generated in response to many G-protein or tyrosine kinase-linked receptor activators including drugs [7,8]. RyR may be activated pharmacologically (e.g., caffeine), by Ca2+ influx from outside the cell in the process of Ca2+-induced Ca2+ release (CICR), or when the stores Ca2+ content exceeds normal physiological values, that is in store overload [2,9–12].Activation of either Ca2+ influx or Ca2+ release results in an increase of the cytoplasmic Ca2+ concentration ([Ca2+]c) from the resting value of ~100 nM to ~1 μM for many seconds throughout the cell, and transiently (e.g., 100 ms) to much higher values (e.g., 50 µM) in small parts of the cytoplasm close to sites of influx or Ca2+ release. These local Ca2+ signals begin with the opening of one or a few channels, allowing a large flux of the ion into the cytoplasm. Influx to the cytoplasm via voltage-dependent Ca2+ channels occurs at rates of ~0.6 million Ca2+ ions per second per channel (0.2 pA current). The influx generates a significant local concentration gradient near the channel in which [Ca2+] declines from ~10 μM to ~100 nM over a few hundred nanometers from the plasma membrane [2,13–17]. Voltage-dependent Ca2+ channel open time is brief (~1 ms) and the gradient dissipates rapidly with rates of change in the subplasma membrane space on the order of ~5000 μM s−1 [2] as compared to a much slower rate of ~0.5 μM s−1 in the bulk cytoplasm [2] after a global [Ca2+] rise [18,19]. The large difference in rate of decline in the subplasma membrane space and bulk cytoplasm arise because local changes are driven mostly by buffering and diffusion while the slower rate of decline in bulk cytoplasm is determined by pumps. High local [Ca2+] and the rapid rates of change near channels may target processes with rapid Ca2+ binding kinetics to selectively activate particular functions [20–23]. The high local [Ca2+] signals arising from influx also, in turn, may activate IP3R or RyR to amplify the local signals or propagate through the cell as global signals with slower but more widespread effects [24–30]. The transition of signals from those involving single to multiple channels and from local to global Ca2+ increases creates a multitude of signals with various locations, magnitudes and time courses [31–34] so that various cellular biological responses may be selectively activated.It is acknowledged that a major way that Ca2+ signaling specifically targets particular biological processes is by increases in concentration of the ion being selectively localized to certain regions of the cell (Figure 9.1) [36,37]. In native smooth muscle cells, mitochondria contribute to the localization of Ca2+ signals and to the modulation of the amplitude of Ca2+ signals [38–42]. Mitochondria regulate these local signals by the organelles’ ability to take up and release the ion. Ca2+ uptake occurs through the mitochondrial Ca2+ uniporter while efflux is mediated by the mitochondrial Na+/Ca2+ exchanger. Mitochondrial Ca2+ uptake and efflux may regulate cytoplasmic Ca2+ concentrations both directly and indirectly. Direct regulation occurs by alteration of bulk Ca2+ levels (Figures 9.2 and 9.3) [18,40,44–47]. Indirect regulation occurs as a result of mitochondrial influence on the activity of SR or plasma membrane Ca2+ channels. This chapter describes how the structure and positioning of mitochondria contribute to the control of Ca2+ signaling, including a previously unrecognized ability of the position of the organelles to increase local Ca2+ entry via voltage-dependent Ca2+ channels.