PHIL 2015 Chapter Notes - Chapter 9.2: Nicotinic Acetylcholine Receptor, Alpha Helix, Potassium Channel
23 May 2020
School
Department
Course
Professor
structure of the cys-loop ligand-gated ion
voltage (Em) to obtain/quantify the relation between voltage and number of open
channels (open probability).
2) Discuss what is known about the structure of the cys-loop ligand-gated ion-
channels, which include nicotinic and GABAA receptor-channels.
2.1) Discuss what has been inferred from analysis of protein structure about the
physical nature of these ion channels (e.g number and nature of subunits, structure
of transmembrane, intracellular, extracellular domains)
Cys-loop ligand gated ion channels form a major class of ligand gated channels and include
the Nicotinic Ach and GABA receptors. These receptors are similar in structure and consist
of 5 homologous subunits arranged in a pentameric fashion. Within each subunit, there is
a large extracellular N-terminus, a short extracellular C-terminus, and an extracellular site
for N-glycosylation.Within the N-terminus there are 2 cys residues separated by 13 amino
acids which have disulfide linkages to form a highly conserved 15 residue loop.
There are 4 transmembrane domains of alpha helices, which are designated M1-M4. The
M3 and M4 domain are partial alpha helices and form a longer intracellular loop that
contains a Camp dependent serine phosphorylation site. The M2 domain, which forms a
full alpha helix, lines the channel and plays a role in determining the channel's conductance
and selectivity. M1 and M2 undergo conformational changes and play a role in the gating
process.
The 5 subunits arrange in a pentameric fashion with the M2 -helices facing the pore.
The subunits come together to form a large vestibule on the extracellular side that
contains excess charged amino acid residues. The vestibule then converges into the
narrow transmembrane pore. This is the basis for the physical nature of the selectivity
filter in that is narrow and contains an abundance of charged residues on the outer side.
2.2) Describe how these channels can discriminate between anions and cations and
between ions of different sizes.
GABA discriminates between ions of different charges via its narrow pore in that ions
too big to fit through the narrow pore will not be selected. In addition, they also
discriminate between cations and ions based on the excess charge in the “vestibule
area”. For example, the excess negative charges in the vestibule of nicotinic receptors
produces a cation selective channel while the excess positive charge in the vestibule
of GABA receptors selects for anions.
The inner channel pore of the receptors is lined by five transmembrane M2 alpha
helices, one from each subunit. In the nicotinic receptors, the M2 helices are
composed largely of hydrophobic or uncharged polar amino acids, butnegatively
charged aspartate or glutamate residues are located at each end, near the
Document Summary
2. 1) discuss what has been inferred from analysis of protein structure about the physical nature of these ion channels (e. g number and nature of subunits, structure of transmembrane, intracellular, extracellular domains) Cys-loop ligand gated ion channels form a major class of ligand gated channels and include the nicotinic ach and gaba receptors. These receptors are similar in structure and consist of 5 homologous subunits arranged in a pentameric fashion. There are 4 transmembrane domains of alpha helices, which are designated m1-m4. M3 and m4 domain are partial alpha helices and form a longer intracellular loop that contains a camp dependent serine phosphorylation site. The m2 domain, which forms a full alpha helix, lines the channel and plays a role in determining the channel"s conductance and selectivity. M1 and m2 undergo conformational changes and play a role in the gating process. The 5 subunits arrange in a pentameric fashion with the m2 -helices facing the pore.
