Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Sci. Signal., 14 December 2010
Vol. 3, Issue 152, p. ec378
[DOI: 10.1126/scisignal.3152ec378]

EDITORS' CHOICE

NEUROSCIENCE Neuronal ER Stress

Nancy R. Gough

Science Signaling, AAAS, Washington, DC 20005, USA

Calcium plays key roles in neuronal signaling; One source of calcium is the endoplasmic reticulum (ER), dysfunction of which has been associated with neurological disorders. Two groups explore how neurons respond to ER stress. Narayanan et al. found that depletion of intracellular calcium stores triggered a reduction in neuronal excitability that was specifically localized to the somatic region in mouse hippocampal slice preparations, which they propose may represent a neuroprotective response to cell stress (see Schmidt and Ehrlich). In a related article, Higo et al. found that ER stress caused altered calcium signaling in neurons by impairing the activity of ER-resident calcium-release channels—the inositol trisphosphate receptors (IP3Rs)—and that reduced abundance of the IP3R1 enhanced neuronal cell death in response to ER stress.

Narayanan et al. used an ER calcium pump inhibitor to deplete intracellular calcium stores and recorded electrophysiological properties of neurons in hippocampal slices. They found that depletion of the stores caused a prolonged reduction in neuronal excitability that was detected in the perisomatic region but not in the dendrites. The electrophysiological changes suggested an increase in h current, a nonselective cationic current, and the reduction in neuronal excitability was blocked by the addition of an inhibitor of the h channel. Unexpectedly, the reduction in neuronal excitability was greater at depolarized voltages, which is not typical of the known properties of the h current. With a 3D, multicompartmental neuronal model, the authors performed simulations that suggested that an increase in functional somatic h channels, along with a depolarizing shift in their gating properties, could explain the reduced perisomatic excitability; these predictions were verified experimentally with the slice preparations. The reduction in excitability was blocked by a calcium chelator, indicating that it required increased intracellular calcium. Inhibition of voltage-gated calcium channels did not block the reduction in excitability, but it did require IP3Rs and store-operated calcium channels, because it was blocked by selective antagonists of either of these channels. Inhibition of protein kinase A also prevented the reduction in excitability, suggesting that activation of the store-operated calcium response and release of ER calcium triggered a pathway involving PKA, a known modulator of h current. The authors propose that intrinsic reduction in neuronal activity would serve as a protective mechanism in response to pathological conditions that cause store depletion.

Higo et al. examined the role of IP3R1 in neuronal response to ER stress. They induced ER stress with the glycosylation inhibitor tunicamycin, the reducing agent dithiothreitol (DTT), or the ER calcium pump inhibitor thapsigargin. Injection of mice with tunicamycin caused an increase in pyknotic (apoptotic) Purkinje neurons in the brains of IP3R1+/– mice relative to the brains of wild-type mice, and in cultured HeLa cells knockdown of IP3R1 caused an increase in apoptotic cells in response to any of the three ER stressors. Calcium imaging studies with a neuroblastoma cell line (N1E-115) and primary cultured neurons showed that DTT or tunicamycin caused a reduction in IP3R1 activity. Multiple experimental paradigms indicated that the ER chaperone GRP78 interacted with the intralumenal domain of IP3R1 (in cell lines, primary cultured neurons, and brain) and that it competed with another ER protein, ERp44, for binding to IP3R1. In a mouse model of Huntington’s disease, a neurodegenerative disease, coimmunoprecipitation experiments showed that the interaction between IP3R1 and GRP78 was reduced in various regions of the brain. With experiments in cultured HeLa, COS-7, and N1E-115 cells, the authors showed that knockdown of GRP78 compromised IP3R1 activity but did not inhibit IP3R2 or IP3R3. Cross-linking and gel filtration experiments indicated that GRP78 promoted the assembly of tetrameric receptors, which is required for activity, and experiments with tunicamycin or thapsigargin showed that ER stress reduced the amount of tetrameric IP3R1. Thus, ER stress appears to compromise calcium signaling by IP3R1s by reducing the interaction with the ER chaperone GRP78 that is needed for proper subunit assembly of the channel. Together, these two studies suggest that ER calcium signaling plays key roles in the neuronal response to ER stress.

R. Narayanan, K. J. Dougherty, D. Johnston, Calcium store depletion induces persistent perisomatic increases in the functional density of h channels in hippocampal pyramidal neurons. Neuron 68, 921–935 (2010). [Online Journal]

T. Higo, K. Hamada, C. Hisatsune, N. Nukina, T. Hashikawa, M. Hattori, T. Nakamura, K. Mikoshiba, Mechanism of ER stress-induced brain damage by IP3 receptor. Neuron 68, 865–878 (2010). [Online Journal]

S. Schmidt, B. E. Ehrlich, Unloading intracellular calcium stores reveals regionally specific functions. Neuron 68, 806–808 (2010). [Online Journal]

Citation: N. R. Gough, Neuronal ER Stress. Sci. Signal. 3, ec378 (2010).



To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882