A sodium channel signaling complex: modulation by associated receptor protein tyrosine phosphatase β

Bharucha

Proc. Natl. Acad. Sci. U.S.A.

et al. 2002

Self Cite

171

182

Sodium channel ␤-subunits modulate channel gating, assembly, and cell surface expression in heterologous cell systems. We generated ␤2 ؊/؊ mice to investigate the role of ␤2 in control of sodium channel density, localization, and function in neurons in vivo. Measurements of [ 3 H]saxitoxin (STX) binding showed a significant reduction in the level of plasma membrane sodium channels in ␤2 ؊/؊ neurons. The loss of ␤2 resulted in negative shifts in the voltage dependence of inactivation as well as significant decreases in sodium current density in acutely dissociated hippocampal neurons. The integral of the compound action potential in optic nerve was significantly reduced, and the threshold for action potential generation was increased, indicating a reduction in the level of functional plasma membrane sodium channels. In contrast, the conduction velocity, the number and size of axons in the optic nerve, and the specific localization of Na v1.6 channels in the nodes of Ranvier were unchanged. ␤2 ؊/؊ mice displayed increased susceptibility to seizures, as indicated by reduced latency and threshold for pilocarpine-induced seizures, but seemed normal in other neurological tests. Our observations show that ␤2-subunits play an important role in the regulation of sodium channel density and function in neurons in vivo and are required for normal action potential generation and control of excitability.auxiliary subunits ͉ gene targeting ͉ epilepsy ͉ action potential conduction

Section: Differential Susceptibility To Seizures Induced By Ip Injementioning

confidence: 89%

“…␤-subunits are also involved in homophilic (5) and heterophilic (6) cell adhesion and in interactions with extracellular matrix and cell adhesion molecules (7)(8)(9), ankyrin (5,(9)(10)(11), and receptor tyrosine phosphatase-␤ (RPTP␤; ref. 12).…”

mentioning

confidence: 99%

Reduced sodium channel density, altered voltage dependence of inactivation, and increased susceptibility to seizures in mice lacking sodium channel β2-subunits

Bharucha

Proc. Natl. Acad. Sci. U.S.A.

et al. 2002

Self Cite

171

182

Journal of Biological Chemistry

“…Peak Na ϩ current amplitude in cultured hippocampal neurons is reduced upon activation of dopamine (D1) receptors via cAMP-dependent protein kinase that is anchored to the ␣-subunit by the channel partner AKAP15 (12,13). Receptor protein-tyrosine phosphatase ␤ interacts with brain sodium channels, phosphorylates tyrosine residue(s) of the channels, and causes a depolarizing shift in the voltage dependence of inactivation of recombinant Na v 1.2 (14). The Ca 2ϩ -binding protein calmodulin interacts with the C terminus of Na v 1.2 (15), Na v 1.5, Na v 1.4 (16,17), and Na v 1.6 1 and modulates the Na ϩ currents in an isoform-specific manner.…”

mentioning

confidence: 99%

Modulation of the Cardiac Sodium Channel Nav1.5 by Fibroblast Growth Factor Homologous Factor 1B

Liu

Dib‐Hajj

Renganathan

et al. 2003

147

We have previously shown that fibroblast growth factor homologous factor 1B (FHF1B), a cytosolic member of the fibroblast growth factor family, associates with the sensory neuron-specific channel Na v 1.9 but not with the other sodium channels present in adult rat dorsal root ganglia neurons. We show in this study that FHF1B binds to the C terminus of the cardiac voltage-gated sodium channel Na v 1.5 and modulates the properties of the channel. The N-terminal 41 amino acid residues of FHF1B are essential for binding to Na v 1.5, and the conserved acidic rich domain (amino acids 1773-1832) in the C terminus of Na v 1.5 is sufficient for association with this factor. Binding of the growth factor to recombinant wild type human Na v 1.5 in human embryonic kidney 293 cells produces a significant hyperpolarizing shift in the voltage dependence of channel inactivation. An aspartic acid to glycine substitution at position 1790 of the channel, which underlies one of the LQT-3 phenotypes of cardiac arrythmias, abolishes the interaction of the Na v 1.5 channel with FHF1B. This is the first report showing that interaction with a growth factor can modulate properties of a voltage-gated sodium channel.

Journal of Biological Chemistry

“…Brain ␣-subunits are phosphorylated at specific serine/threonine sites by protein kinase A that is anchored to the ␣-subunit via AKAP15 (11,12). Receptor protein-tyrosine phosphatase (RPTP␤) interacts with brain ␣-subunits via its carbonic anhydrase homology extracellular domain and its intracellular phosphatase domain and phosphorylates tyrosine residues of the channel (13). Peripheral sensory neurons in the dorsal root ganglia (DRG) 1 and trigeminal ganglia produce pharmacologically and physiologically distinguishable Na ϩ currents, some of which are sensitive to the neurotoxin tetrodotoxin (TTX-S), and others which are resistant to this toxin (TTX-R).…”

mentioning

confidence: 99%

Fibroblast Growth Factor Homologous Factor 1B Binds to the C Terminus of the Tetrodotoxin-resistant Sodium Channel rNav1.9a (NaN)

Liu

Dib‐Hajj

Waxman

2001

121

124

In this study we demonstrate a direct interaction between a cytosolic fibroblast growth factor family member and a sodium channel. A yeast two-hybrid screen for proteins that associate with the cytoplasmic domains of the tetrodotoxin-resistant sodium channel rNa v 1.9a (NaN) led to the identification of fibroblast growth factor homologous factor 1B (FHF1B), a member of the fibroblast growth factor family, as an interacting partner of rNa v 1.9a. FHF1B selectively interacts with the C-terminal region but not the other four intracellular segments of rNa v 1.9a. FHF1B binds directly to the Cterminal polypeptide of rNa v 1.9a both in vitro and in mammalian cell lines. The N-terminal 5-77 amino acid residues of FHF1B are essential for binding to rNa v 1.9a. FHF1B did not interact with C termini of two other sodium channels hNa v 1.7a (hNaNE) and rNa v 1.8a (SNS), which share 50% similarity to the C-terminal polypeptide of rNa v 1.9a. FHF1B is the first growth factor found to bind specifically to a sodium channel. Although the functional significance of this interaction is not clear, FHF1B may affect the rNa v 1.9a channel directly or by recruiting other proteins to the channel complex. Alternatively, it is possible that rNa v 1.9a may help deliver this factor to the cell membrane, where it exerts its function.