Aging Cell (2007) 6, pp285–296 Blackwel RE PublisVhingLtdIEW 2+ Age-dependent changes in Ca homeostasis in peripheral neurones: implications for changes in function Doi: 10.1111/j.1474-9726.2007.00298.x John N. Buchholz,1 Erik J. Behringer,1 William J. Pottorf,2 William J. Pearce1 and Conwin K. Vanterpool3 1Department of Physiology and Pharmacology, Loma Linda University, School of Medicine, Loma Linda, CA 92350, USA 2Department Scientific Affairs, Astra Zeneca 1800 Concord Pike Wilmington, DE 19850, USA 3Department of Biological Sciences, Carter Hall, Alabama A & M, 4900 Meridian Street, Normal, AL 35762, USA Summary Calcium ions represent universal second messengers within neuronal cells integrating multiple cellular functions, such as release of neurotransmitters, gene expression, prolif- eration, excitability, and regulation of cell death or apoptotic pathways. The magnitude, duration and shape of stimulation-evoked intracellular calcium ([Ca2+]i) tran- sients are determined by a complex interplay of mech- anisms that modulate stimulation-evoked rises in [Ca2+]i that occur with normal neuronal function. Disruption of any of these mechanisms may have implications for the function and health of peripheral neurones during the aging process. This review focuses on the impact of advancing age on the overall function of peripheral adrenergic neurones and how these changes in function may be linked to age-related changes in modulation of [Ca2+]i regulation. The data in this review suggest that normal aging in peripheral autonomic neurones is a subtle process and does not always result in dramatic deterio- ration in their function. We present studies that support the idea that in order to maintain cell viability peripheral neurones are able to compensate for an age-related decline in the function of at least one of the neuronal calcium- buffering systems, smooth endoplasmic reticulum calcium ATPases, by increased function of other calcium-buffering systems, namely, the mitochondria and plasmalemma calcium extrusion. Increased mitochondrial calcium uptake Correspondence John N. Buchholz, Department of Physiology and Pharmacology, Loma Linda University, School of Medicine, Loma Linda, CA, 92350, USA. Tel.: 909 558 4564; fax 909 558 0119; e-mail: jbuchholz@llu.edu Accepted for publication 19 March 2007 Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation. may represent a ‘weak point’ in cellular compensation as this over time may contribute to cell death. In addition, we present more recent studies on [Ca2+]i regulation in the form of the modulation of release of calcium from smooth endoplasmic reticulum calcium stores. These stud- ies suggest that the contribution of the release of calcium from smooth endoplasmic reticulum calcium stores is altered with age through a combination of altered ryanodine receptor levels and modulation of these receptors by neuronal nitric oxide containing neurones. Key words: age and calcium homeostasis; calcium buffer- ing; superior cervical ganglion. Introduction Calcium is widely recognized as a universal second messenger within neuronal cells and integrates multiple cellular functions. These include release of neurotransmitters, gene expression, proliferation, excitability and regulation of cell death or apoptotic pathways (Malenka et al., 1989; Choi, 1992; Berridge, 1995, 1998; Clapham, 1995; Ginty, 1997; Wuytack et al., 2002). At rest, neurones maintain a large intracellular calcium ([Ca2+]i) concentration gradient between the extracellular milieu and cytosol. In peripheral neurones, calcium signaling begins with the opening of L and N and some R type calcium channels, allowing calcium to flow from outside of the cell into the cytosol (Kostyuk, 1989; Trouslard et al., 1993; Vanterpool et al., 2005). Much of this signal is damped by calcium-buffering proteins. However, calcium signaling initiated by calcium influx is sustained by the rapid release of calcium from smooth endoplasmic reticulum (SER) calcium stores. This process is known as calcium-induced calcium release (CICR) and is mediated by calcium acting on ryanodine receptor (RyR) channels (Belan et al., 1993; Verkhratsky & Shmigol, 1996; Usachev & Thayer, 1997, 1999a,b; Verkhratsky & Petersen, 1998; Akita & Kuba, 2000). Following a rapid rise in [Ca2+]i, and depending on the mag- nitude of the [Ca2+]i transient, complex buffering systems that include multiple calcium-buffering proteins, smooth endo- plasmic reticulum calcium ATPases (SERCA), mitochondrial calcium uptake, plasmalemma calcium ATPases (PMCA) and the sodium–calcium exchanger (Na+/Ca2+), work together to reduce [Ca2+]i from its peak levels, and restore [Ca2+]i back to resting levels (Werth & Thayer, 1994; Buchholz et al., 1996; Werth et al., 1996; Usachev & Thayer, 1999a; Pottorf et al., 2000a,c, 2002; Wuytack et al., 2002). In particular, the CICR process is dependent on buffering by SERCA as this buffering not only © 2007 Loma Linda University Journal compilation © Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland 2007 285