title: 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.
authors.affiliation: Department of Cell Biology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Piccoli
authors.forename: Urs
authors.initials: U
authors.lastname: Rutishauser
authors.forename: Juan L
authors.initials: JL
authors.lastname: Brusés
mesh_terms: D036002:ADP Ribose Transferases / Q000494:pharmacology; D000577:Amides / Q000494:pharmacology; D000818:Animals; D001905:Botulinum Toxins / Q000494:pharmacology; D015820:Cadherins / Q000737:chemistry / Q000502:physiology*; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000502:physiology*; D020013:Calcium Signaling / Q000502:physiology*; D002448:Cell Adhesion; D002642:Chick Embryo; D002645:Chickens; D005726:Ganglia, Parasympathetic / Q000166:cytology / Q000201:enzymology / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D015640:Ion Channel Gating / Q000502:physiology; D017136:Ion Transport; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D018408:Patch-Clamp Techniques; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D017434:Protein Structure, Tertiary; D011725:Pyridines / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000502:physiology; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D000577:Amides; D015820:Cadherins; D015220:Calcium Channels; D047908:Intracellular Signaling Peptides and Proteins; D011725:Pyridines; D011993:Recombinant Fusion Proteins; C108830:Y 27632; D036002:ADP Ribose Transferases; C063007:exoenzyme C3, Clostridium botulinum; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D001905:Botulinum Toxins; D020742:rhoA GTP-Binding Protein; D002118:Calcium