Related Experiment Video
Updated: Jul 18, 2026
11:31
Antigens Protected Functional Red Blood Cells By The Membrane Grafting Of Compact Hyperbranched Polyglycerols
Published on: January 2, 2013
HERG is protected from pharmacological block by alpha-1,2-glucosyltransferase function
Tadashi Nakajima1, Kenshi Hayashi, Prakash C Viswanathan
1Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6602, USA.
The Journal of Biological Chemistry
|December 26, 2006
Summary
The KCR1 protein protects the heart by reducing drug sensitivity of the HERG channel, preventing acquired long QT syndrome (aLQTS). This protection involves glucosyltransferase activity, offering a new way to prevent drug-induced arrhythmias.
Area of Science:
- Cardiology
- Molecular Biology
- Pharmacology
Background:
- The human ether-à-go-go-related gene (HERG) protein regulates cardiac repolarization (I(Kr)) and is an unintended target for many drugs.
- Inadvertent HERG channel block causes acquired long QT syndrome (aLQTS), a major reason for drug withdrawal by regulatory agencies.
- Understanding protective factors against aLQTS is crucial for developing safer therapeutics across various medical fields.
Purpose of the Study:
- To investigate the role of the K(+) channel regulatory protein KCR1 in protecting HERG channels from drug-induced block.
- To elucidate the molecular mechanism by which KCR1 reduces HERG channel drug sensitivity.
Main Methods:
- Comparative analysis of KCR1 and yeast alpha-1,2-glucosyltransferase ALG10.
- Assessing HERG channel block by dofetilide in the presence of KCR1 and ALG10.
- Investigating the effect of KCR1 in cells with inhibited glycosylation (tunicamycin) or deficient in glycosylation (Lec1 cells).
- Utilizing yeast complementation assays and computational modeling.
Main Results:
- KCR1 significantly reduces HERG channel drug sensitivity, similar to ALG10.
- KCR1's protective effect is dependent on cellular glycosylation pathways.
- KCR1 functions as an alpha-1,2-glucosyltransferase, protecting HERG channels indirectly, not by direct glycosylation.
- Computational modeling suggests KCR1 expression is protective against cardiac arrhythmias.
Conclusions:
- KCR1 protects against acquired long QT syndrome (aLQTS) through its alpha-1,2-glucosyltransferase activity.
- This mechanism involves modulating HERG channel drug response via glycosylation pathways.
- Findings reveal a novel therapeutic target for preventing drug-induced arrhythmias.
Related Concept Videos
01:12GPCR Desensitization
G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
01:24Oligosaccharide Assembly
Protein glycosylation starts in the ER lumen and continues in the Golgi apparatus. Glycosyltransferases catalyze the addition of sugar molecules or glycosylation of proteins. Usually, these enzymes add sugars to the hydroxyl groups of selected serine or threonine residues to form O-linked glycans or the amino groups of asparagine residues to form N-linked glycans. Different positions on the same polypeptide chain can contain differently linked glycans.
Multiple sugar molecules that may or may...
Multiple sugar molecules that may or may...
01:09GPCRs Regulate Adenylyl Cylase Activity
Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of cells.
Two...
Two...
01:32Export of Misfolded Proteins out of the ER
After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
01:24Phase II Reactions: Glucuronidation
Glucuronidation, a pivotal phase II biotransformation process, involves the coupling of glucuronic acid to a drug or xenobiotic. Given its widespread occurrence and critical role in drug metabolism, it's considered the most crucial phase II reaction. It enhances the water solubility of substances, aiding their expulsion from the body. The driving force behind these reactions is a group of enzymes known as UDP-glucuronosyltransferases (UGTs). UGTs facilitate the transfer of a glucuronic acid...
01:22Activation and Inactivation of G Proteins
Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high affinity and are together...