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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
