286 Age and Ca2+ homeostasis in peripheral neurones, J. N. Buchholz et al. Fig. 1 (A) Representation of mechanisms that modulate stimulation-evoked [Ca2+]i transients in peripheral adrenergic nerves. Depolarization increases [Ca2+]i by rapid calcium influx through voltage-gated calcium channels. Calcium is rapidly attenuated via calcium-binding proteins and the residual calcium signal acting on ryanodine receptors (RyR) evoke release of calcium from the endoplasmic reticulum known as calcium-induced calcium release (CICR). The elevation in [Ca2+]i is controlled by a dynamic interplay of buffering systems: (1) smooth endoplasmic reticulum calcium ATPases (SERCA) sequestration into the ER that serves to buffer and refill ER calcium stores thus maintaining the ability of the neurone to undergo repetitive CICR; (2) mitochondrial calcium uptake by a H+/Ca2+ uniporter; (3) removal of calcium via plasma membrane calcium ATPases (PMCA) pumps and the Na+/Ca2+ exchanger. Plum dotted lines represent calcium influx and release pathways that elevate [Ca2+]i. Light blue dashed lines represent calcium-buffering pathways that control increases in [Ca2+]i and restoration to resting levels. (B) Model illustrating the hypothesis that advancing age in the absence of pathology, results in a subtle decline in the control of [Ca2+]i. Compensation by other control mechanisms may allow neurones to adapt to an age-related decline in control of [Ca2+]i. Specifically, this model illustrates the mechanisms that lead to elevated [Ca2+]i in aged peripheral adrenergic neurones. The rise in [Ca2+]i mediated via calcium influx and release from the SER is buffered by SERCA whose function declines with age (broken red line). In response to the decline in SERCA function mitochondria, PMCA and Na+/Ca2+ exchanger compensate (thick red solid lines) for the decline in SERCA function by increasing Ca2+ uptake and removal so as to preserve overall neuronal viability. In addition, the decline in SERCA function may possibly alter ER Ca2+ filling levels, which may have consequences for sustained CICR in senescent neurones. participates in control of [Ca2+]i levels, but serves as a refilling of endoplasmic reticulum calcium stores (Vanterpool et al., 2005). These complex processes are illustrated in Fig. 1(A). Overall, the magnitude, duration, and shape of stimulation- evoked [Ca2+]i transients are determined by a complex interplay of mechanisms that increase, buffer, and return these transients to resting levels. Disruption of any of these mechanisms may have implications for the function and health of peripheral neu- rones during the aging process. This review will focus 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 levels. In addition, other consequences of age-related alterations in the modulation of [Ca2+]i in peripheral adrenergic neurones will be addressed. Data from studies on peripheral sensory and central neurones will also be incorporated into the discussion, as these models lend insight into the function of adrenergic neurones during the aging process. Why are adrenergic nerves arising from the superior cervical ganglion an important study model? The superior cervical ganglion (SCG) has been suggested to be a peripheral neuroendocrine center because of the plethora of tissues that receive adrenergic input from this source (Cardinali et al., 1981). The SCG has been shown to be an important modulator of cardiac function that relays cardioregulatory impulses from the central nervous system (CNS) to the SCG axons terminating in the heart that release noradrenaline (NA) © 2007 Loma Linda University Journal compilation © Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland 2007