N-Cadherin Juxtamembrane Domain Modulates Voltage-Gated Ca²⁺Current via RhoA GTPase and Rho-Associated Kinase

Abstract

The juxtamembrane domain (JMD) of N-cadherin cytoplasmic tail is an important regulatory region of the clustering and adhesion activities of the protein. In addition, the JMD binds a diversity of proteins capable of modifying intracellular processes including cytoskeletal rearrangement mediated by Rho GTPases. These GTPases also function as regulators of voltage-activated calcium channels, which in turn modulate neuronal excitability. The present study was designed to determine whether there is a direct functional link, via Rho GTPase, between the N-cadherin JMD and these voltage-activated channels. It was found that the infusion of the soluble JMD into chick ciliary neurons causes a substantial decrease in the amplitude of the high-threshold voltage-activated (HVA) calcium current. The activation time is increased while the inactivation process is reduced, suggesting that the decreased current amplitude reflects a reduction in the number of channels available to open. This effect was reversed by inhibition of RhoA or its downstream effector, Rho-associated kinase (ROCK). Because ROCK determines the active state of myosin, these results suggest that the modulation of HVA by the JMD could be mediated by changes in the status of the actin-myosin cytoskeleton.

Cadherins in development: cell adhesion, sorting, and tissue morphogenesis

“…The juxta-membrane domain of N-cadherin has also been shown to be important in regulating voltage-gated calcium currents in chick ciliary neurons (Piccoli et al 2004), although the mechanism is unknown. Most recently, evidence for N-cadherin function in short-term plasticity in glutamatergic neurons was reported (Jungling et al 2006).…”

RhoA GTPase and F-actin Dynamically Regulate the Permeability of Cx43-made Channels in Rat Cardiac Myocytes

“…In rat ventricular myocytes, neither inhibition of RhoA nor its activation noticeably affected immunolabeled N-cadherin, but conversely Rho family proteins, which are known to be signal transducers downstream of cadherin (75) adherens junctions, might then influence GJIC. N-cadherin for example was found to be able to modulate voltage-gated Ca 2ϩ channels via activation of RhoA and its downstream effector, ROCK (79).…”

Endogenous Rho-Kinase Signaling Maintains Synaptic Strength by Stabilizing the Size of the Readily Releasable Pool of Synaptic Vesicles

“…The actin-myosin cytoskeletal structure, in turn, regulates distribution and trafficking of synaptic vesicles within presynaptic terminals and neurotransmitter release at synapses (Trifaró and Vitale, 1993;Dillon and Goda, 2005). The idea of a presynaptic locus for a ROCK-mediated modulation of neurotransmission is also supported by the findings that ROCK inhibits N-type Ca 2ϩ channels (Piccoli et al, 2004), which are involved in excitation-secretion coupling at central synapses (Dunlap et al, 1995), and Kv1.2 channels, which are often localized at synaptic compartments (Cachero et al, 1998). In our experimental conditions, ROCK inhibition strongly reduced amplitudes of eEPSCs AMPA and eIPSCs GABA in HMNs but did not attenuate mEPSCs AMPA or whole-cell responses to glutamate pulses.…”

“…However, whether ROCK regulates neuronal physiology by modulating intrinsic membrane properties and/or afferent input drive to neurons remains unknown so far. In this way, ROCK regulates several ionic channels (Li et al, 2002;Piccoli et al, 2004;Staruschenko et al, 2004;Iftinca et al, 2007).…”