Reduced G protein-coupled signaling efficiency in retinal rod outer segments in response to n-3 fatty acid deficiency.
The fatty acid (FA) docosahexaenoic acid (DHA, 22: 6n-3) is highly enriched in membrane phospholipids of the central nervous system and retina. Loss of DHA because of n-3 FA deficiency leads to suboptimal function in learning, memory, olfactory-based discrimination, spatial learning, and visual acuity. G protein-coupled receptor (GPCR) signal transduction is a common signaling motif in these neuronal pathways. Here we investigated the effect of n-3 FA deficiency on GPCR signaling in retinal rod outer segment (ROS) membranes isolated from rats raised on n-3-adequate or -deficient diets. ROS membranes of second generation n-3 FA-deficient rats had approximately 80% less DHA than n-3-adequate rats. DHA was replaced by docosapentaenoic acid (22:5n-6), an n-6 FA. This replacement correlated with desensitization of visual signaling in n-3 FA-deficient ROS, as evidenced by reduced rhodopsin activation, rhodopsin-transducin (G(t)) coupling, cGMP phosphodiesterase activity, and slower formation of metarhodopsin II (MII) and the MII-G(t) complex relative to n-3 FA-adequate ROS. ROS membranes from n-3 FA-deficient rats exhibited a higher degree of phospholipid acyl chain order relative to n-3 FA-adequate rats. These findings reported here provide an explanation for the reduced amplitude and delayed response of the electroretinogram a-wave observed in n-3 FA deficiency in rodents and nonhuman primates. Because members of the GPCR family are widespread in signaling pathways in the nervous system, the effect of reduced GPCR signaling due to the loss of membrane DHA may serve as an explanation for the suboptimal neural signaling observed in n-3 FA deficiency.
Niu
Shui-Lin
SL
Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Rockville, Maryland 20852, USA.
Mitchell
Drake C
DC
Lim
Sun-Young
SY
Wen
Zhi-Ming
ZM
Kim
Hee-Yong
HY
Salem
Norman
N
Litman
Burton J
BJ
D000818:Animals; D004281:Docosahexaenoic Acids / Q000378:metabolism; D004596:Electroretinography; D005136:Eye Proteins / Q000378:metabolism*; D015525:Fatty Acids, Omega-3 / Q000378:metabolism*; D005260:Female; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D008563:Membrane Lipids / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D012374:Rod Cell Outer Segment / Q000378:metabolism*; D015398:Signal Transduction; D015293:Transducin
D005136:Eye Proteins; D015525:Fatty Acids, Omega-3; C034809:GNAT1 protein, human; C488950:Gnat1 protein, rat; D008563:Membrane Lipids; D004281:Docosahexaenoic Acids; D010727:Phosphoric Diester Hydrolases; D020962:Heterotrimeric GTP-Binding Proteins; D015293:Transducin