![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Department of Pharmacology, University of Pennsylvania School of
Medicine, Philadelphia, Pennsylvania (J.C., K.W.),
Groupe de Recherche
en Thérapeutique Anticancéreuse, The effects of several N-sulfonyl-polyamines, including
N1-dansyl-spermine (N1-DnsSpm) and
N1-(n-octanesulfonyl)-spermine
(N1-OsSpm), were studied at recombinant
N-methyl-D-aspartate (NMDA) receptors expressed
in Xenopus laevis oocytes. N1-DnsSpm and
N1-OsSpm inhibited NMDA receptors and were ~1000-fold
more potent than spermine in oocytes voltage-clamped at 
70 mV. Block
by N1-DnsSpm and N1-OsSpm was strongly voltage
dependent, being more pronounced at hyperpolarized membrane potentials.
With the Woodhull model of voltage-dependent channel block, the values
of Kd(0) were 779 µM, 882 µM, and 7.4 mM and those of z
were 2.58, 2.57, and 1.07 for
N1-DnsSpm, N1-OsSpm, and spermine,
respectively. This suggests that an increase in the voltage dependence
of block together with an increase in affinity contributes to the
increased potencies of N1-DnsSpm and N1-OsSpm
compared with spermine. Sensitivity to N1-DnsSpm was
reduced by mutation NR1(N616Q) and was increased by mutations
NR1(N616G) and NR2A(N615G). The NR1(N616G) and NR2A(N615G) mutations
decreased the Kd(0) value of
N1-DnsSpm without affecting z, whereas the NR1(N616Q)
mutation reduced z. These mutations may alter the accessibility of
part of the polyamine binding site within the channel pore or directly alter the properties of that site. Block by N1-DnsSpm (0.3 µM) was almost complete at 100 mV, and there was no relief of block at extreme negative membrane potentials (100 to
200 mV) at wild-type NR1/NR2A channels. In contrast, block by
N1-DnsSpm was partially relieved at extreme negative
potentials at receptors containing NR1(N616G) or NR2A(N615G),
suggesting that N1-DnsSpm can permeate these mutant
channels but not wild-type NR1/NR2A channels. This is hypothesized to
be due to an increase in the pore size of channels containing
NR1(N616G) or NR2A(N615G), which allows passage of the bulky head group
of N1-DnsSpm. In contrast to N1-DnsSpm,
N1-OsSpm could easily permeate wild-type NR1/NR2A channels,
presumably because the head group of N1-OsSpm can pass
through the narrowest part of the channel pore. N-Sulfonyl-polyamines such as N1-DnsSpm and
N1-OsSpm represent a new class of polyamine antagonists
with which to study glutamate receptor ion channels.
Copyright © by The American Society for Pharmacology and Experimental Therapeutics
This article has been cited by other articles:
|
|
 |
|
  L. Jin, H. Sugiyama, M. Takigawa, D. Katagiri, H. Tomitori, K. Nishimura, N. Kaur, O. Phanstiel IV, M. Kitajima, H. Takayama, et al. Comparative Studies of Anthraquinone- and Anthracene-Tetraamines as Blockers of N-Methyl-D-aspartate Receptors J. Pharmacol. Exp. Ther., January 1, 2007; 320(1): 47 - 55. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Musa, E. Fenn, M. Crye, J. Gemel, E. C. Beyer, and R. D. Veenstra Amino terminal glutamate residues confer spermine sensitivity and affect voltage gating and channel conductance of rat connexin40 gap junctions J. Physiol., June 15, 2004; 557(3): 863 - 878. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Kashiwagi, I. Tanaka, M. Tamura, H. Sugiyama, T. Okawara, M. Otsuka, T. N. Sabado, K. Williams, and K. Igarashi Anthraquinone Polyamines: Novel Channel Blockers to Study N-Methyl-D-Aspartate Receptors J. Pharmacol. Exp. Ther., June 1, 2004; 309(3): 884 - 893. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Williams, M. Dattilo, T. N. Sabado, K. Kashiwagi, and K. Igarashi. Pharmacology of delta 2 Glutamate Receptors: Effects of Pentamidine and Protons J. Pharmacol. Exp. Ther., May 1, 2003; 305(2): 740 - 748. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Kashiwagi, T. Masuko, C. D. Nguyen, T. Kuno, I. Tanaka, K. Igarashi, and K. Williams Channel Blockers Acting at N-Methyl-D-aspartate Receptors: Differential Effects of Mutations in the Vestibule and Ion Channel Pore Mol. Pharmacol., March 1, 2002; 61(3): 533 - 545. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Masuko, K. Kashiwagi, T. Kuno, N. D. Nguyen, A. J. Pahk, J.-i. Fukuchi, K. Igarashi, and K. Williams A Regulatory Domain (R1-R2) in the Amino Terminus of the N-Methyl-D-Aspartate Receptor: Effects of Spermine, Protons, and Ifenprodil, and Structural Similarity to Bacterial Leucine/Isoleucine/Valine Binding Protein Mol. Pharmacol., June 1, 1999; 55(6): 957 - 969. [Abstract] [Full Text]
|
|
|
|
 |
|
 R. Dingledine, K. Borges, D. Bowie, and S. F. Traynelis The Glutamate Receptor Ion Channels Pharmacol. Rev., March 1, 1999; 51(1): 7 - 62. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. G. Vassylyev, H. Tomitori, K. Kashiwagi, K. Morikawa, and K. Igarashi Crystal Structure and Mutational Analysis of the Escherichia coli Putrescine Receptor. STRUCTURAL BASIS FOR SUBSTRATE SPECIFICITY J. Biol. Chem., July 10, 1998; 273(28): 17604 - 17609. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Bahring and M. L Mayer An analysis of philanthotoxin block for recombinant rat GluR6(Q) glutamate receptor channels J. Physiol., June 15, 1998; 509(3): 635 - 650. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Williams, A. J. Pahk, K. Kashiwagi, T. Masuko, N. D. Nguyen, and K. Igarashi The Selectivity Filter of the N-Methyl-D-Aspartate Receptor: A Tryptophan Residue Controls Block and Permeation of Mg2+ Mol. Pharmacol., May 1, 1998; 53(5): 933 - 941. [Abstract] [Full Text]
|
|
|
|
|
|
K. Igarashi, A. Shirahata, A. J. Pahk, K. Kashiwagi, and K. Williams Benzyl-polyamines: Novel, Potent N-Methyl-D-aspartate Receptor Antagonists J. Pharmacol. Exp. Ther., November 1, 1997; 283(2): 533 - 540. [Abstract] [Full Text]
|
|
|
|
|
|
K. Kashiwagi, A. J. Pahk, T. Masuko, K. Igarashi, and K. Williams Block and Modulation of N-Methyl-D-Aspartate Receptors by Polyamines and Protons: Role of Amino Acid Residues in the Transmembrane and Pore-Forming Regions of NR1 and NR2 Subunits Mol. Pharmacol., October 1, 1997; 52(4): 701 - 713. [Abstract] [Full Text]
|
|
 |
 |
 |
|
 |
 |
 |
