Ion channel accessory proteins: functions, physiology, and implications for pharmacology

Published on August 29, 2024   34 min

A selection of talks on Neurology

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0:00
Hi. My name is Mike Maher. I'm a Director in Neuropsychiatry Discovery for Janssen Research & Development in San Diego, California. Today I'm going to be talking about ion channel accessory proteins and how they function with respect to pharmacology and physiology, and how that relates to drug discovery.
0:21
First, I'm going to talk in general terms about the scope of the field. Then I'm going to do a deep dive into one specific accessory protein that has led to clinical candidates for epilepsy. Then I'll zoom back out to talk about our learnings from this program and how they relate to future drug discovery.
0:40
Before we get started, I'd like to tell you about a few other related Henry Stewart talks that will help to put this information into context. The first two are very closely related. The talks by Stuart Cull-Candy and Javier Diaz Alonso speak to AMPA receptors and accessory proteins from different aspects and are very helpful in putting this information into context. Then in a larger sense for how they relate to synapses, the talks by Graham Collingridge, Johannes Hell and Jonathan Hanley help to explain how these proteins are involved in making and maintaining synapsis.
1:19
First of all, what is an accessory protein? The basic definition is that it's a protein that is more than transiently associated with a primary functional or Alpha subunit, and that shows a functional impact on that primary subunit. The definition is rather vague, partly because there are so many different types of interaction that can happen. But for my purposes, and as it relates to drug discovery, this definition is sufficient. A large number of accessory proteins have been identified for transmembrane proteins and additional ones continue to be found along the way. Accessory proteins seem to be the rule rather than the exception for Alpha subunits, and they serve a wide variety of functions. Here, I show a few examples. One is for HCN channels. You see here several accessory proteins. The main one is TRIP8b, that's very closely related to trafficking but also having a functional impact on how those channels are gated by cyclic AMP. There are other receptors including the IRAGs, which can alter the voltage and kinetics of the HCN channels and also KCNE2, which is involved with gating and KCR1, which can alter the activation voltage. In terms of the nicotinics, most of the accessory proteins that have been discovered are involved with trafficking. The one exception to that is BARP, which seems to be translocated to the surface of the receptor with the nicotinic and affects its function. We also have a number of other classes of

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