Extracellular Calcium Matters, Too

Science Signaling  04 Mar 2008:
Vol. 1, Issue 9, pp. ec83
DOI: 10.1126/stke.19ec83

During the development of the nervous system, neurons extend processes that navigate the microenvironment by responding to various guidance molecules; many of the signaling pathways involved depend on intracellular Ca2+. The extracellular calcium-sensing receptor (CaSR) is found in organs known to regulate Ca2+ homeostasis; however, CaSR is also found in areas of the brain, such as the hippocampus, and on sympathetic neurons in the peripheral nervous system. This led Vizard et al. to investigate whether CaSR might play a role in neuronal development. The authors used real-time polymerase chain reaction assays and immunofluorescence microscopy to show that the abundance of CaSR in the superior cervical ganglion (SCG) of the mouse peaks on embryonic day 18 (E18) before declining within a few days of birth. This coincides with a transient increase in the concentration of free extracellular Ca2+ ([Ca2+]o) in the embryo and with the period during which sympathetic axons innervate their targets. E18 SCG neurons cultured with nerve growth factor developed longer and more branched neurites when exposed to 2.3 mM [Ca2+]o than did those cultured in 0.7 mM [Ca2+]o. Expression in neurons of a dominant-negative CaSR inhibited the effect of [Ca2+]o on neurite growth and branching in vitro. The retinas of Casr−/− mice showed decreased innervation by sympathetic axons compared with those of wild-type mice. Expression of dominant-negative CaSR in hippocampal pyramidal neurons in organ cultures resulted in reduced dendrite outgrowth and branching compared with that in control cultures. As Spitzer discusses in commentary, these data suggest that CaSR controls neurite outgrowth and branching in response to [Ca2+]o, which acts here as a first rather than second messenger.

T. N. Vizard, G. W. O’Keeffe, H. Gutierrez, C. H. Kos, D. Riccardi, A. M. Davies, Regulation of axonal and dendritic growth by the extracellular calcium-sensing receptor. Nat. Neurosci. 11, 285-291 (2008). [PubMed]

N. C. Spitzer, Calcium: First messenger. Nat. Neurosci. 11, 243-244 (2008). [PubMed]