Nanion Webinars


March 2021 - Evaluation of Melanocortin Compounds at the MC4R-Kir7.1 Complex and CiPA Based Evaluation of Proarrhythmic Risk

210311 SP384 March 11 Webinar CRL UMich V1
Presenters: 

Ciria Hernandez, MD, Ph.D
(Assistant Research Scientist  - University of Michigan Life Sciences Institute)

Title: 
High-Throughput Functional Evaluation of Melanocortin Compounds at the MC4R-Kir7.1 Complex: Biased Signaling at the Melanocortin 4 Receptor


Abstract: 

Melanocortin 4 receptors (MC4R) are G-protein coupled receptors (GPCR) that mediate a variety of physiological processes critical for energy homeostasis. Loss-of-function MC4R mutations are linked to early-onset syndromic obesity. MC4R is the first GPCR reported to functionally directly interact with the inward rectifier potassium channel Kir7.1. In the paraventricular nucleus of the hypothalamus, MC4R activation leads to Kir7.1 closure causing neuronal depolarization and satiety, whereas its inhibition promotes channel opening leading to membrane hyperpolarization and hunger. The discovery of a G-protein independent pathway for MC4R signaling through Kir7.1 opened new venues for the exploration of new signaling pathways by GPCRs."

Yuri Kuryshev
(Principle Scientist - Charles River Laboratories)

Title: 
CiPA Based Evaluation of Proarrhythmic Risk Using the SyncroPatch 384PE

Abstract:

Cardiac arrhythmias are a limiting factor for development of new drugs in any therapeutic area. Proarrhythmic risk prediction modeling is a contemporary approach for cardiac safety and the modeling requires reliable experimental data for drug effects on four major cardiac ion channel currents – hERG, Cav1.2 (peak and late) and Nav1.5 (late). We have validated these channel assays on SyncroPatch 384PE platform and applied them to evaluation several drugs with questionable proarrhythmic safety.

Date: 11. March 2021
Time: 5:00 PM CET / 11:00 AM EST / 8AM PST

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210318 Randy Katherine Webinar
Presenters: 


Randy Stockbridge and Katherine Henzler-Wildman
(Assistant Professor - University of Michigan | Assistant Professor - University of Wisconsin-Madison)

Session 1: 
Understanding drug efflux – Small Multidrug Resistance Family - Stoichiometry and
Specificity


Abstract:

The transporters of the SMR family catalyze multidrug and toxin efflux in bacteria, energetically driven by proton influx. Not only are these proteins interesting in the context of novel antimicrobial strategies but due to their small size, they are valuable tools for a better understanding of transport mechanisms and substrate specificity.

In the first session of the transporter webinar series, we have the opportunity to learn from two experts in the field, Randy Stockbridge and Katherine Henzler-Wildman, about their approaches and insights working with this transporter family.

Randy Stockbridge


Title: 
Determining transport stoichiometry using SSME

Abstract:

Transporters from the small multidrug resistance (SMR) family provide broad resistance to environmental biocides, driving the spread of multidrug resistance cassettes among bacterial populations. Understanding substrate specificity is essential to understand this process. Using solid-supported membrane electrophysiology, we measure the transport of different substrates by SMR family members, and show that promiscuous transport of hydrophobic substituted cations is a general feature of all SMR transporters, including those whose primary physiological role is in bacterial nitrogen metabolism.

Katherine Henzler-Wildman

Title: 
Basis of promiscuity in small multidrug resistance transporters

Transport stoichiometry can provide great insight into the mechanism and function of ion-coupled transporters. Traditional reversal potential assays are a reliable, general method for determining the transport stoichiometry of ion-coupled transporters, but the time and material costs of this technique hinder investigations of transporter behavior under multiple experimental conditions. Our prior work on EmrE has demonstrated that it is not a tightly coupled transporter and that the net transport stoichiometry is likely to vary with pH and substrate identity. This has motivated us to develop an SSME-based assay for assessing transport stoichiometry that is rapid and easily adaptable to different substrates and pH conditions. Here we present results for Gdx and CLC-Ec1, two well-characterized transporters that demonstrate the success of our approach. Our SSME-based method reproduces the fixed 2H+:1 guanidinium+ antiport stoichiometry of Gdx, the 1H+:2Cl- antiport stoichiometry of CLC-ec1, and loose proton:nitrate coupling for CLC-ec1. This method requires only small amounts of transporter and provides a fast, easy method to characterize transport stoichiometry under varied conditions, which will facilitate future mechanistic and functional studies of ion-coupled transporters.

Date: 18. March 2021
Time: 
4:00 PM CET / 10:00 AM EST 

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