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Syntaxin-1A Inhibits the KATP Channel Through Interaction with Distinct Sites Along the Nucleotide-binding Folds of Sulfonylurea Receptor 1Chang, Nathan 13 January 2010 (has links)
The KATP channel is a key regulator of the pancreatic β-cell, effectively linking metabolic status to electrical activity. Syntaxin-1A has been previously reported by our lab to both bind and inhibit the KATP channel via the nucleotide-binding folds (NBFs). The purpose of this thesis project was to elucidate the precise regions within the NBFs responsible for the Syn-1A- KATP interaction. In vitro binding assays revealed that Syn-1A associates with the Walker domains of both NBF1 and NBF2. Furthermore, site directed mutagenesis of the conserved lysine in Walker A of both NBFs abolishes Syn-1A affinity for this region. Electrophysiological recordings indicate that channel inhibition was mediated primarily through interaction with NBF1-Walker B and both Walkers of NBF2. Based on these results, we propose a model by which Syn-1A acts as an inhibitory clamp on the KATP channel, effectively buffering minor fluctuations in ATP/ADP concentration to prevent unnecessary channel activity.
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Syntaxin-1A Inhibits the KATP Channel Through Interaction with Distinct Sites Along the Nucleotide-binding Folds of Sulfonylurea Receptor 1Chang, Nathan 13 January 2010 (has links)
The KATP channel is a key regulator of the pancreatic β-cell, effectively linking metabolic status to electrical activity. Syntaxin-1A has been previously reported by our lab to both bind and inhibit the KATP channel via the nucleotide-binding folds (NBFs). The purpose of this thesis project was to elucidate the precise regions within the NBFs responsible for the Syn-1A- KATP interaction. In vitro binding assays revealed that Syn-1A associates with the Walker domains of both NBF1 and NBF2. Furthermore, site directed mutagenesis of the conserved lysine in Walker A of both NBFs abolishes Syn-1A affinity for this region. Electrophysiological recordings indicate that channel inhibition was mediated primarily through interaction with NBF1-Walker B and both Walkers of NBF2. Based on these results, we propose a model by which Syn-1A acts as an inhibitory clamp on the KATP channel, effectively buffering minor fluctuations in ATP/ADP concentration to prevent unnecessary channel activity.
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The Regulatory Role of Syntaxin 1 N-terminal Conformation in Vesicle Priming and Exocytosis / Die Regulation der Vesikelreifung und -Freisetzung durch Syntaxin 1Rah, Jong-Cheol 02 November 2004 (has links)
No description available.
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Syntaxin-1A Inhibits Cardiac ATP-Sensitive Potassium Channels by Direct Interaction with Distinct Domains within Sulphonylurea Receptor 2A Nucleotide-Binding FoldsChao, Christin Chih Ting 13 January 2010 (has links)
KATP channels couple cell metabolic status to the membrane excitability by sensing the cytoplasmic ATP/ADP ratio. Present studies examined how conserved motifs (Walker A (WA), signature sequence (L), and Walker B (WB)) within each NBF of SUR2A bind to Syn-1A to affect its actions on cardiac KATP channels. In vitro binding experiments illustrated that Syn-1A binds cardiac SUR2A at WA and L of NBF-1 and WA, L, and WB of NBF-2. Electrophysiology experiments on stably expressing SUR2A/Kir6.2 cell-lines showed that only L and WB of NBF-1 and all three NBF-2 motifs could abrogate the inhibitory effect of Syn-1A on SUR2A/KATP channels. These results lead me to hypothesize that more independent motif in NBF-2 can bind and abrogate Syn-1A’s inhibition than NBF-1 on SUR2A/KATP channels. A corollary postulate is that Syn-1A acts as a scaffold to secure the NBF-1 and -2 in dimer conformation required for SUR2A to modulate Kir6.2 gating.
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Syntaxin-1A Inhibits Cardiac ATP-Sensitive Potassium Channels by Direct Interaction with Distinct Domains within Sulphonylurea Receptor 2A Nucleotide-Binding FoldsChao, Christin Chih Ting 13 January 2010 (has links)
KATP channels couple cell metabolic status to the membrane excitability by sensing the cytoplasmic ATP/ADP ratio. Present studies examined how conserved motifs (Walker A (WA), signature sequence (L), and Walker B (WB)) within each NBF of SUR2A bind to Syn-1A to affect its actions on cardiac KATP channels. In vitro binding experiments illustrated that Syn-1A binds cardiac SUR2A at WA and L of NBF-1 and WA, L, and WB of NBF-2. Electrophysiology experiments on stably expressing SUR2A/Kir6.2 cell-lines showed that only L and WB of NBF-1 and all three NBF-2 motifs could abrogate the inhibitory effect of Syn-1A on SUR2A/KATP channels. These results lead me to hypothesize that more independent motif in NBF-2 can bind and abrogate Syn-1A’s inhibition than NBF-1 on SUR2A/KATP channels. A corollary postulate is that Syn-1A acts as a scaffold to secure the NBF-1 and -2 in dimer conformation required for SUR2A to modulate Kir6.2 gating.
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