Mitchell Goldfarb

Publications (86) View all

• Source

  Available from: Mitchell Goldfarb

  Article: Voltage-gated sodium channel-associated proteins and alternative mechanisms of inactivation and block.

  Mitchell Goldfarb
  [show abstract] [hide abstract]
  ABSTRACT: Voltage-gated sodium channels mediate inward current of action potentials upon membrane depolarization of excitable cells. The initial transient sodium current is restricted to milliseconds through three distinct channel-inactivating and blocking mechanisms. All pore-forming alpha subunits of sodium channels possess structural elements mediating fast inactivation upon depolarization and recovery within milliseconds upon membrane repolarization. Accessory subunits modulate fast inactivation dynamics, but these proteins can also limit current by contributing distinct inactivation and blocking particles. A-type isoforms of fibroblast growth factor homologous factors (FHFs) bear a particle that induces long-term channel inactivation, while sodium channel subunit Navβ4 employs a blocking particle that rapidly dissociates upon membrane repolarization to generate resurgent current. Despite their different physiological functions, the FHF and Navβ4 particles have similarity in amino acid composition and mechanisms for docking within sodium channels. The three competing channel-inactivating and blocking processes functionally interact to regulate a neuron's intrinsic excitability.
  Cellular and Molecular Life Sciences CMLS 09/2011; 69(7):1067-76. · 6.57 Impact Factor
• Source

  Available from: Mitchell Goldfarb

  Article: Behavioral and cerebellar transmission deficits in mice lacking the autism-linked gene islet brain-2.

  Joanna Giza, Michael J Urbanski, Francesca Prestori, Bhaswati Bandyopadhyay, Annie Yam, Victor Friedrich, Kevin Kelley, Egidio D'Angelo, Mitchell Goldfarb
  [show abstract] [hide abstract]
  ABSTRACT: Deletion of the human SHANK3 gene near the terminus of chromosome 22q is associated with Phelan-McDermid syndrome and autism spectrum disorders. Nearly all such deletions also span the tightly linked IB2 gene. We show here that IB2 protein is broadly expressed in the brain and is highly enriched within postsynaptic densities. Experimental disruption of the IB2 gene in mice reduces AMPA and enhances NMDA receptor-mediated glutamatergic transmission in cerebellum, changes the morphology of Purkinje cell dendritic arbors, and induces motor and cognitive deficits suggesting an autism phenotype. These findings support a role for human IB2 mutation as a contributing genetic factor in Chr22qter-associated cognitive disorders.
  Journal of Neuroscience 11/2010; 30(44):14805-16. · 7.11 Impact Factor
• Source

  Available from: Mitchell Goldfarb

  Article: Long-term inactivation particle for voltage-gated sodium channels.

  Katarzyna Dover, Sergio Solinas, Egidio D'Angelo, Mitchell Goldfarb
  [show abstract] [hide abstract]
  ABSTRACT: Action potential generation is governed by the opening, inactivation, and recovery of voltage-gated sodium channels. A channel's voltage-sensing and pore-forming α subunit bears an intrinsic fast inactivation particle that mediates both onset of inactivation upon membrane depolarization and rapid recovery upon repolarization. We describe here a novel inactivation particle housed within an accessory channel subunit (A-type FHF protein) that mediates rapid-onset, long-term inactivation of several sodium channels. The channel-intrinsic and tethered FHF-derived particles, both situated at the cytoplasmic face of the plasma membrane, compete for induction of inactivation, causing channels to progressively accumulate into the long-term refractory state during multiple cycles of membrane depolarization. Intracellular injection of a short peptide corresponding to the FHF particle can reproduce channel long-term inactivation in a dose-dependent manner and can inhibit repetitive firing of cerebellar granule neurons. We discuss potential structural mechanisms of long-term inactivation and potential roles of A-type FHFs in the modulation of action potential generation and conduction.
  The Journal of Physiology 10/2010; 588(Pt 19):3695-711. · 4.72 Impact Factor
• Source

  Available from: Mitchell Goldfarb

  Article: FRS2 PTB domain conformation regulates interactions with divergent neurotrophic receptors.

  Kelley S Yan, Miklos Kuti, Sherry Yan, Shiraz Mujtaba, Amjad Farooq, Mitchell P Goldfarb, Ming-Ming Zhou
  [show abstract] [hide abstract]
  ABSTRACT: Membrane-anchored adaptor proteins FRS2alpha/beta (also known as SNT-1/2) mediate signaling of fibroblast growth factor receptors (FGFRs) and neurotrophin receptors (TRKs) through their N-terminal phosphotyrosine binding (PTB) domains. The FRS2 PTB domain recognizes tyrosine-phosphorylated TRKs at an NPXpY (where pY is phosphotyrosine) motif, whereas its constitutive association with FGFR involves a receptor juxtamembrane region lacking Tyr and Asn residues. Here we show by isothermal titration calorimetry that the FRS2alpha PTB domain binding to peptides derived from TRKs or FGFR is thermodynamically different. TRK binding is largely enthalpy-driven, whereas the FGFR interaction is governed by a favorable entropic contribution to the free energy of binding. Furthermore, our NMR spectral analysis suggests that disruption of an unstructured region C-terminal to the PTB domain alters local conformation and dynamics of the residues at the ligand-binding site, and that structural disruption of the beta8-strand directly weakens the PTB domain association with the FGFR ligand. Together, our new findings support a molecular mechanism by which conformational dynamics of the FRS2alpha PTB domain dictates its association with either fibroblast growth factor or neurotrophin receptors in neuronal development.
  Journal of Biological Chemistry 06/2002; 277(19):17088-94. · 4.77 Impact Factor
• Source

  Available from: Mitchell Goldfarb

  Article: SNT-1/FRS2alpha physically interacts with Laloo and mediates mesoderm induction by fibroblast growth factor.

  J Hama, H Xu, M Goldfarb, D C Weinstein
  [show abstract] [hide abstract]
  ABSTRACT: Members of the fibroblast growth factor (FGF) ligand family play a critical role in mesoderm formation in the frog Xenopus laevis. While many components of the signaling cascade triggered by FGF receptor activation have been identified, links between these intracellular factors and the receptor itself have been difficult to establish. We report here the characterization of Xenopus SNT-1 (FRS2alpha), a scaffolding protein previously identified as a mediator of FGF activity in other biological contexts. SNT-1 is widely expressed during early Xenopus development, consistent with a role for this protein in mesoderm formation. Ectopic SNT-1 induces mesoderm in Xenopus ectodermal explants, synergizes with low levels of FGF, and is blocked by inhibition of Ras activity, suggesting that SNT-1 functions to transmit signals from the FGF receptor during mesoderm formation. Furthermore, dominant-inhibitory SNT-1 mutants inhibit mesoderm induction by FGF, suggesting that SNT-1 is required for this process. Expression of dominant-negative SNT-1 in intact embryos blocks mesoderm formation and dramatically disrupts trunk and tail development, indicating a requirement for SNT-1, or a related factor inhibited by the mutant construct, during axis formation in vivo. Finally, we demonstrate that SNT-1 physically associates with the Src-like kinase Laloo, and that SNT-1 activity is required for mesoderm induction by Laloo, suggesting that SNT-1 and Laloo function as components of a signaling complex during mesoderm formation in the vertebrate.
  Mechanisms of Development 01/2002; 109(2):195-204. · 2.83 Impact Factor