Painful nerve injury decreases sarco-endoplasmic reticulum Ca2+-ATPase activity in axotomized sensory neurons
Highlights
► SERCA regulates [Ca2+]c at rest and during recovery from activity. ► Repeated neuronal activation slows SERCA function. ► Injury reduces SERCA function in small sensory neurons.
Introduction
Intracellular Ca2+ levels ([Ca2+]c) regulate neuronal excitability, release of neurotransmitters, cell differentiation and apoptosis (Ghosh and Greenberg, 1995, Mata and Sepulveda, 2005). Thus, dysregulation of [Ca2+]c signaling leads to diverse neuropathological conditions (Fernyhough and Calcutt, 2010, Gleichmann and Mattson, 2011, Stutzmann and Mattson, 2011). Neuronal activation triggers an influx of Ca2+ through voltage-gated Ca2+ channels (VGCCs), requiring buffering, sequestration, and ultimately Ca2+ efflux to reestablish Ca2+ homeostasis. Efflux pathways include the plasma membrane Ca2+-ATPase (PMCA) and the Na+/Ca2+ exchanger (NCX) (Benham et al., 1992, Suzuki et al., 2002, Usachev et al., 2002, Guerini et al., 2005, Lytton, 2007), while sequestration of Ca2+ into organelle compartments is achieved by the sarco-endoplasmic reticulum Ca2+ ATPase (SERCA), mitochondrial Ca2+ uniporter, and secretory pathway Ca2+/Mn2+-ATPases (SPCA) (Fierro et al., 1998, Wuytack et al., 2002, Verkhratsky, 2004, Verkhratsky, 2005, Usachev et al., 2006, Sepulveda et al., 2007, Brini and Carafoli, 2009).
We have previously demonstrated that painful peripheral nerve injury is associated with aberrant Ca2+ signaling in peripheral sensory neurons after axotomy, including reduced resting [Ca2+]c (Fuchs et al., 2005), diminished activity-induced transients (Fuchs et al., 2007), and accelerated store-operated Ca2+ channel (SOCC) function (Gemes et al., 2011). Also, releasable Ca2+ stored in the endoplasmic reticulum (ER) is depleted and the concentration of Ca2+ in the ER lumen ([Ca2+]L) is depressed by injury in small sensory neurons (Rigaud et al., 2009). The [Ca2+]L is set by the dynamic balance between SERCA and constitutive Ca2+ leakage from the ER through poorly defined channels (Camello et al., 2002). Our prior finding of normal Ca2+ release channel function after injury (Rigaud et al., 2009) suggests compromised SERCA performance as the cause of decreased [Ca2+]L in injured neurons.
SERCA is the principal high-affinity sequestration pathway for Ca2+ that enters during neuronal activation (Verkhratsky, 2005), and accounts for the most of intracellular uptake during low amplitude [Ca2+]c transients that are insufficient to engage mitochondrial buffering (Usachev et al., 2006). Normal SERCA function is required to maintain intracellular stores that provide releasable Ca2+, which in turn regulates neuronal excitability (Gemes et al., 2011). SERCA dysfunction contributes to numerous pathological conditions, including diabetic axonopathy (Zherebitskaya et al., 2012), Ca2+ overload during neuronal ischemia (Larsen et al., 2005, Henrich and Buckler, 2008), age-associated neuronal degeneration (Pottorf et al., 2000a, Pottorf et al., 2000b), excitotoxicity (Fernandes et al., 2008), ER stress and apoptosis (Mengesdorf et al., 2001, Verkhratsky, 2004, Gallego-Sandin et al., 2011). Little is known about the modulation of SERCA function after peripheral nerve injury or its role in chronic pain.
To characterize the effect of neuronal trauma, we have measured SERCA function in rats subjected to spinal nerve ligation (SNL) (Kim and Chung, 1992, Hogan et al., 2004), which provides neuronal populations that are axotomized (in the fifth lumbar dorsal root ganglion – L5 DRG), versus the neighboring fourth DRG (L4) neurons that are intact but exposed to inflammation caused by degeneration of the detached distal L5 fiber segments (Gold, 2000). To isolate SERCA, we blocked PMCA, which is the main efflux pathway in neurons (Benham et al., 1992, Usachev et al., 2002).
Section snippets
Animals
All methods and use of animals were approved by the Medical College of Wisconsin Institutional Animal Care and Use Committee. Male Sprague–Dawley rats (Taconic Farms Inc., Hudson, NY, USA) were housed individually in a room maintained at 22 ± 0.5 °C and constant humidity (60 ± 15%) with an alternating 12-h-light–dark cycle. Food and water were available ad libitum throughout the experiments.
Injury model
Rats weighing 150–180 g were subjected to SNL modified from the original technique (Kim and Chung, 1992).
Results
The frequency of hyperalgesia responses after noxious punctate mechanical stimulation in SNL rats (40 ± 4%, n = 27) was greater than in control rats (0 ± 0%, n = 35; p < 0.001). The accuracy of the SNL surgery was confirmed at the time of tissue harvest in all SNL animals.
Discussion
Several findings emerge from our examination of SERCA function in control and injured sensory neurons. SERCA operates constitutively in these neurons even while they are inactive and participates in the regulation of resting [Ca2+]c. Upon neuronal activation, SERCA contributes to recovery of the Ca2+ transient. When PMCA function is eliminated, SERCA aids in buffering unopposed Ca2+ influx. The particular susceptibility of axotomized L5 neurons to [Ca2+]c elevation after PMCA block in resting
Acknowledgments
The study was supported by National Institutes of Health Grant NS-42150 (to Q.H.H.) and DA-K01-024751 (to H.-E.W.). V.N.U. and J.J.R. are employees of Merck and Co., Inc. and may own stock and/or stock options in the company.
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