These tools will no longer be maintained as of December 31, 2024. Archived website can be found here. PubMed4Hh GitHub repository can be found here. Contact NLM Customer Service if you have questions.


Pubmed for Handhelds

PUBMED FOR HANDHELDS

Search MEDLINE/PubMed

  • Title: Coupled and uncoupled gating and desensitization effects by pore domain mutations in GABA(A) receptors.
    Author: Scheller M, Forman SA.
    Journal: J Neurosci; 2002 Oct 01; 22(19):8411-21. PubMed ID: 12351715.
    Abstract:
    GABA(A) receptors are allosteric ligand-gated ion channels. Agonist-induced gating and desensitization have been proposed to be coupled via pore domain structures. Mutations at two alpha1 subunit pore-domain (transmembrane domain 2) residues enhance GABA sensitivity, leucine-to-threonine at position 264 (9'), and serine-to-isoleucine at position 270 (15'). We investigated the role of these residues in gating, desensitization, and deactivation of alpha1beta2gamma2L GABA(A) receptors using rapid GABA concentration jumps and patch-clamp electrophysiology. GABA EC(50) values for alpha1(L264T)beta2gamma2L and alpha1(S270I)beta2gamma2L currents were, respectively, approximately 80-fold and 13-fold lower than the wild-type EC50. Unlike wild type, both mutant receptors displayed significant picrotoxin-sensitive currents in the absence of GABA, indicating that they enhance gating efficacy. Both mutants displayed current activation rates that matched wild type at 1 microm GABA and above. Desensitization of wild-type and alpha1(S270I)beta2gamma2L currents displayed indistinguishable rates and amplitudes, whereas alpha1(L264T)beta2gamma2L currents desensitized extremely slowly. Deactivation of wild-type currents displayed two rates and slowed after partial desensitization, whereas currents from both mutants deactivated slowly with single rate constants that were unaffected by desensitization. These results indicate that both alpha1(L264T) and alpha1(S270I) mutations increase the gating efficacy of receptors by slowing channel closing, which accounts for nearly all of the similar changes that they produce in macrocurrent dynamics. Because the alpha1(S270I) mutation uncouples its gating effects from those on rapid desensitization, these two processes are necessarily associated with movements of distinct receptor structures (gates). The effects of the alpha1(L264T) mutation suggest that the conserved leucines may play a role in gating-desensitization coupling.
    [Abstract] [Full Text] [Related] [New Search]