Journal
BIOPHYSICAL JOURNAL
Volume 88, Issue 5, Pages 3286-3299Publisher
CELL PRESS
DOI: 10.1529/biophysj.104.051664
Keywords
-
Categories
Ask authors/readers for more resources
We have developed a homology model of the GABA(A) receptor, using the subunit combination of alpha 1 beta 2 gamma 2, the most prevalent type in the mammalian brain. The model is produced in two parts: the membrane-embedded channel domain and the extracellular N-terminal domain. The pentameric transmembrane domain model is built by modeling each subunit by homology with the equivalent subunit of the heteropentameric acetylcholine receptor transmembrane domain. This segment is then joined with the extracellular domain built by homology with the acetylcholine binding protein. The all-atom model forms a wide extracellular vestibule that is connected to an oval chamber near the external surface of the membrane. A narrow, cylindrical transmembrane channel links the outer segment of the pore to a shallow intracellular vestibule. The physiological properties of the model so constructed are examined using electrostatic calculations and Brownian dynamics simulations. A deep energy well of similar to 80 kT accommodates three Cl- ions in the narrow transmembrane channel and seven Cl- ions in the external vestibule. Inward permeation takes place when one of the ions queued in the external vestibule enters the narrow segment and ejects the innermost ion. The model, when incorporated into Brownian dynamics, reproduces key experimental features, such as the single-channel current-voltage-concentration profiles. Finally, we simulate the gamma 2 K289M epilepsy inducing mutation and examine Cl- ion permeation through the mutant receptor.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available