Boundary lipids in the nicotinic acetylcholine receptor microenvironment.
The structural and functional properties of the nicotinic acetylcholine receptor (AChR), the archetype molecule in the superfamily of Cys-looped ligand-gated ion channels, are strongly dependent on the lipids in the vicinal microenvironment. The influence on receptor properties is mainly exerted by the AChR-vicinal ("shell" or "annular") lipids, which occur in the liquid-ordered phase as opposed to the more disordered and "fluid" bulk membrane lipids. Fluorescence studies from our laboratory have identified discrete sites for fatty acids, phospholipids, and cholesterol on the AChR protein, and electron-spin resonance spectroscopy has enabled the establishment of the stoichiometry and selectivity of the shell lipid for the AChR and the disclosure of lipid sites in the AChR transmembrane region. Experimental evidence supports the notion that the interface between the protein moiety and the adjacent lipid shell is the locus of a variety of pharmacologically relevant processes, including the action of steroids and other lipids. I surmise that the outermost ring of M4 helices constitutes the boundary interface, most suitable to convey the signals from the lipid microenvironment to the rest of the transmembrane region, and to the channel inner ring in particular.
Barrantes
Francisco J
FJ
UNESCO Chair of Biophys. & Mol. Neurobiol. and Institute of Biochemistry, Universidad Nacional del Sur-CONICET, C.C. 857, B8000FWB, Bahía, Blanca, Argentina. rtfjb1@criba.edu.ar
Bermudez
V
V
Borroni
M V
MV
Antollini
S S
SS
Pediconi
M F
MF
Baier
J C
JC
Bonini
I
I
Gallegos
C
C
Roccamo
A M
AM
Valles
A S
AS
Ayala
V
V
Kamerbeek
C
C
D000818:Animals; D002784:Cholesterol / Q000737:chemistry / Q000502:physiology; D005227:Fatty Acids / Q000737:chemistry / Q000502:physiology; D006801:Humans; D007473:Ion Channels / Q000737:chemistry* / Q000187:drug effects / Q000502:physiology*; D008563:Membrane Lipids / Q000737:chemistry* / Q000502:physiology*; D010743:Phospholipids / Q000737:chemistry / Q000502:physiology; D017433:Protein Structure, Secondary; D021122:Protein Subunits / Q000737:chemistry / Q000502:physiology; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000187:drug effects / Q000502:physiology*; D013570:Synaptic Membranes / Q000737:chemistry / Q000187:drug effects / Q000502:physiology
D005227:Fatty Acids; D007473:Ion Channels; D008563:Membrane Lipids; D010743:Phospholipids; D021122:Protein Subunits; D011978:Receptors, Nicotinic; D002784:Cholesterol
Curr Opin Drug Discov Devel. 2003 Sep;6(5):620-32
14579511
Nature. 2007 Jan 4;445(7123):116-9
17167423
Physiol Rev. 2009 Jan;89(1):73-120
19126755
Proc Natl Acad Sci U S A. 1978 Sep;75(9):4329-33
212745
Nature. 2008 Mar 20;452(7185):375-9
18322461
J Biol Chem. 2000 Dec 1;275(48):37333-9
10967108
J Phys Chem B. 2006 Oct 19;110(41):20640-8
17034254
J Biol Chem. 2002 Jan 11;277(2):1249-54
11682474
Biochim Biophys Acta. 1981 Jul 6;645(1):97-101
6266478
Nature. 2009 Jan 1;457(7225):111-4
18987633
Nat Neurosci. 2007 Aug;10(8):953-62
17643119
Brain Res Brain Res Rev. 2004 Dec;47(1-3):71-95
15572164
Biophys J. 1996 Mar;70(3):1275-84
8785283
Biochemistry. 1998 Nov 24;37(47):16653-62
9843433
J Biol Chem. 2008 Aug 1;283(31):21478-86
18511419
Biochemistry. 2007 Mar 20;46(11):3503-12
17319650
J Mol Biol. 2005 Mar 4;346(4):967-89
15701510
Nature. 2001 May 17;411(6835):269-76
11357122
J Am Chem Soc. 2005 Feb 2;127(4):1291-9
15669869
Biochemistry. 2003 Aug 5;42(30):9167-75
12885251