Journal of Molecular Neuroscience

Copyright © 1995 Humana Press inc.

All rights of any nature whatsoever reserved.
ISSN0895-8696/94-95/5(4): 211-217/$5.40

MINIREVIEW

Transmembrane Topology
of the Glutamate Receptors
A Tale of Novel Twists a n d Turns

Thomas E. Hughes
Department of Ophthalmology and Visual Science, Yale University School
of Medicine, PO Box 208061, New Haven CT, 06520-8061
Received March 17, 1995; Revised March 21, 1995; Accepted March 29, 1995

Abstract

The glutamate receptor subunits were first thought to cross the cell membrane four
times in a manner analogous to the neuronal nicotinic acetylcholine, GABAA, and gly-
cine receptors. This model led the field for nearly five years, although it was frequently
in conflict with the data. Recently, comparisons with bacterial proteins, epitope tagging
experiments, and the construction of chimeras has produced a new model of glutamate
receptor topology that is novel and quite unlike any of the other receptors.

Index Entries: Transmembrane regions; glutamate receptor subunits; superfamilies.

Introduction and Heinemann, 1994). One particularly

The last 5 years have produced a tremen-
dous a m o u n t of information on the struc-
ture a n d m o l e c u l a r c o m p o s i t i o n of the
glutamate-gated ion channels of the brain
(reviewed by Nakanishi, 1992; Hollmann
interesting facet of this story has been the
w o r k on d e t e r m i n i n g w h i c h parts of a
receptor subunit are on the inside of the
cell and w h i c h are on the outside. This
study of transmembrane topology is intri-
g u i n g because it reveals h o w d i f f e r e n t

Journal of Molecular Neuroscience 211 Volume 5, t 994/1995

212
ways of comparing sequence information
can p r o d u c e very different models of a
channel-forming protein.
The comparison of protein sequences is
much like any other kind of comparative
anatomy: There exists two fundamentally
different ways of comparing organic form
and interpreting the observed similarity
(Russell, 1982). One school searches for a
common plan. In the early 19th century, the
G e r m a n school of t r a n s c e n d e n t a l mor-
phologists referred to this plan as the arche-
type, a sort of ideal animal. Similarities
s h a r e d by all vertebrates ultimately led
the transcendentalists to propose that all
were variations on one theme. In m o d e r n
terms, the l a n g u a g e of this line of reason-
ing is different, usually invoking concepts
such as evolution from a c o m m o n ances-
tor, but the process of comparison remains
the same.
The other school, in m a n y w a y s best
exemplified by Cuvier, studies form in
order to glean insights into function. The
premise is that form bears a direct relation-
ship to function and that similarities within
or between organisms reflect a commonal-
ity in function. For Cuvier there was only
a limited set of possible solutions to a given
set of functional problems, in his terms con-
ditions of existence, and comparative anat-
omy revealed these solutions. Obviously
the differences between these schools is in
some ways a false dichotomy--observed
similarity need not reflect only evolution-
ary background or function, but this is a
useful framework in the sense that com-
parisons are often biased t o w a r d one or
the other approach, and observed similar-
ity is frequently explained as the result of
either evolutionary consequences or func-
tional ones.
Journal of Molecular Neuroscience
Hughes
The Superfamily Hypothesis:
In Search of the Archetype
In 1989 when Hollmann and coworkers
cloned the first functional glutamate-gated
ion channel (Hollmann et al., 1989), one of
the prevailing ideas was that the ionotropic
receptors of the brain were all members of
a s u p e r f a m i l y of genes ( B a r n a r d et al.,
1987). Indeed, there were m a n y features
s h a r e d by the nicotinic a c e t y l c h o l i n e ,
GABAA, and glycine receptors. Accord-
ingly, the new glutamate receptor subunits
(GluRs) were first compared to the other
r e c e p t o r s u b u n i t s . This r e v e a l e d t h a t
a l t h o u g h the GluRs w e r e m u c h larger,
there w e r e h y d r o p h o b i c r e g i o n s t h a t
could be aligned with the four transmem-
brane regions (TM) of the other subunits
(Hollmann et al., 1989, 1990). This led to a
model of GluR topology analogous to the
other receptor subunits: The N-terminus
was on the outside, the region b e t w e e n
TM1 and TM2 was inside, there was a short
extracellular loop between TM2 and TM3,
a larger intracellular loop extended from
TM3 to TM4, a n d the C - t e r m i n u s w a s
extracellular. This m o d e l w a s q u i c k l y
adopted and repeated throughout the liter-
ature of the next 5 years. As more subunits
were cloned in both this and the N M D A
receptor subunit family, the same scheme
was applied (reviewed by Hollmann and
Heinemann, 1994).
Some of the first data concerning the sub-
units was consistent with the model. A
study of the N-terminus of GluR1 revealed
t w o m u t a t i o n s t h a t a l t e r e d the d o s e -
response r e l a t i o n s h i p s of the receptor,
indicating that this region is an extracellu-
lar d o m a i n involved in agonist b i n d i n g
(Uchino et al., 1992). Studies of the TM2
Volume 5, 1994/1995