N-cadherin modulates voltage activated calcium influx via RhoA, p120-catenin, and myosin-actin interaction

Department of Anatomy and Cell Biology, University of Kansas School of Medicine, Kansas City, 66160, USA.
Molecular and Cellular Neuroscience (Impact Factor: 3.84). 03/2009; 40(3):390-400. DOI: 10.1016/j.mcn.2008.12.007
Source: PubMed


N-cadherin is a transmembrane adhesion receptor that contributes to neuronal development and synapse formation through homophilic interactions that provide structural-adhesive support to contacts between cell membranes. In addition, N-cadherin homotypic binding may initiate cell signaling that regulates neuronal physiology. In this study, we investigated signaling capabilities of N-cadherin that control voltage activated calcium influx. Using whole-cell voltage clamp recording of isolated inward calcium currents in freshly isolated chick ciliary ganglion neurons we show that the juxtamembrane region of N-cadherin cytoplasmic domain regulates high-threshold voltage activated calcium currents by interacting with p120-catenin and activating RhoA. This regulatory mechanism requires myosin interaction with actin. Furthermore, N-cadherin homophilic binding enhanced voltage activated calcium current amplitude in dissociated neurons that have already developed mature synaptic contacts in vivo. The increase in calcium current amplitude was not affected by brefeldin A suggesting that the effect is caused via direct channel modulation and not by increasing channel expression. In contrast, homotypic N-cadherin interaction failed to regulate calcium influx in freshly isolated immature neurons. However, RhoA inhibitors enhanced calcium current amplitude in these immature neurons, suggesting that the inhibitory effect of RhoA on calcium entry is regulated during neuronal development and synapse maturation. These results indicate that N-cadherin modulates voltage activated calcium entry by a mechanism that involves RhoA activity and its downstream effects on the cytoskeleton, and suggest that N-cadherin provides support for synaptic maturation and sustained synaptic activity by facilitating voltage activated calcium influx.

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Available from: Christopher S Theisen, Dec 22, 2014
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    • "Interestingly, when the Fura-2AM reporter was used, steady state levels of intracellular Ca2+ were found to be not affected by substrate coated recombinant N-cadherin suggesting that N-cadherin influences predominantly submembrane Ca2+ levels [40]. Whole cell voltage clamp recordings also showed that homophilic binding of N-cadherin on neuronal membranes to soluble N-cadherin or N-cadherin overexpressed in Chinese hamster ovary (CHO) cells increases amplitudes of Ca2+ currents in ciliary ganglion neurons indicating that homophilic interactions of N-cadherin are sufficient to activate a cellular mechanism that regulates Ca2+ influx [41]. "
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    • "Binding of p120-catenin to cadherins in glutamatergic presynaptic terminals contribute to presynaptic differentiation and clustering of synaptic vesicles (Lee et al., 2008), suggesting that coupling of p120-catenin to N-cadherin in postsynaptic cells may increase the activity of N-cadherin in presynaptic differentiation. As p120-catenin regulates RhoA and voltage-activated calcium influx in cholinergic neurons (Anastasiadis et al., 2000; Piccoli et al., 2004; Marrs et al., 2009), this results suggests that coupling and uncoupling of p120-catenin from N-cadherin may serve as a switch that regulates the activity of N-cadherin and downstream signaling pathways during formation and maturation of cholinergic synapses (Brusés, 2006). "
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    • "egulating the trafficking and localization of AMPA - type or other glutamate receptor subunits ( Coussen et al . , 2002 ; Nuriya and Huganir , 2006 ; Saglietti et al . , 2007 ; Silverman et al . , 2007 ) ; by affecting presynaptic vesicle release ( Bozdagi et al . , 2004 ; Jungling et al . , 2006 ) or by increasing voltage - gated calcium influx ( Marrs et al . , 2009 ) . Consistent with this idea , it has been shown recently that conditional deletion of N - cadherin at mature synapses impairs persistence of theta - induced LTP and LTP - associated spine enlargement at CA1 synapses ( Bozdagi et al . , 2010 ) , as well as reduces spine stability ( Mendez et al . , 2010 ) ."
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