The Role of Docosahexaenoic Acid Containing Phospholipids in Modulating G Protein-Coupled Signaling Pathways: Visual Transduction

Abstract

In order to understand the role of the high levels of docosahexaenoic acid (DHA) in neuronal and retinal tissue, a study of the effect of membrane lipid composition on the visual pathway, a G protein-coupled system, was undertaken. The level of metarhodopsin II (MII) formation was determined to be a function of phospholipid acyl-chain unsaturation, with the highest levels seen in DHA-containing bilayers. Similarly, the rate of coupling of MII to the retinal G protein, Gt, to form a MII-Gt complex, was enhanced in DHA bilayers relative to less unsaturated phospholipids. Complex formation initiates the first stage of amplification in the visual pathway. The activation of the cGMP phosphodiesterase (PDE), the effector enzyme, represents the integrated pathway function. DHA-containing bilayers were found to support PDE levels comparable to those of the rod outer segment (ROS) disk membranes. Inclusion of 30 mol% cholesterol in the reconstituted bilayers had an inhibitory effect on each step in the visual pathway studied. Inclusion of cholesterol reduced MII formation and PDE activity and increased the lag time between the appearance of MII and the formation of the MII-Gt complex. However, signaling in DHA bilayers was far less affected by the addition of cholesterol than in bilayers containing less unsaturated phospholipids. These studies point up the importance of DHA acyl chains in promoting optimal function in G protein-coupled signaling pathways. The results reported here suggest that visual and cognitive deficits observed in n-3 deficiency may result from decreased efficiency in related neurotransmitter and visual signaling pathways in the absence of DHA.

How a small change in retinal leads to G‐protein activation: Initial events suggested by molecular dynamics calculations

“…52,[116][117][118][119][120][121][122][123][124] We can speculate, from our current and previous 121 work about why this may be important. We suggest that the nature of the coupling from the cis-trans activated state to the relaxed state will depend on an ability of the helices to reorient, the sidechains to shift, and the cytoplasmic loops to adjust their relative positions.…”

Mechanisms of action of docosahexaenoic acid in the nervous system

“…This parameter represents the lag time in appearance of the complex after MII has formed and is a measure of the efficiency of the interaction of the receptor and G t protein. This ratio is 1.4 in the native ROS disk membrane, indicating a rapid complex formation after the appearance of MII (106). Complex formation in 18:0,22:6-PC and 18:0,18:1-PC is characterized by ratios of 3.5 and 4.9, respectively.…”

“…At light exposure levels at which 1 in 1000 rhodopsin molecules was activated, ROS disks yielded 87% of their maximal PDE activity. Under similar light exposure conditions, 59 (106). Although not reaching the same activity as native disk membranes, the DHA-containing bilayer yields twice the activity of the monounsaturated bilayer.…”

“…To elucidate the role of n-3 fatty acids in the nervous system and visual process, the phospholipid acyl chain dependence of several steps in the visual transduction pathway was studied (105). This was accomplished by purifying several components of the visual transduction system and reconstituting them in phospholipid vesicles of defined lipid composition (106).…”

The retina is more susceptible than the brain and the liver to the incorporation oftransisomers of DHA in rats consumingtransisomers of alpha-linolenic acid

“…Mechanistic evidences were provided to explain the retinal functional deficits observed in cases of n-3 deficiency and the lower efficiency of DHA replacement by DPA. Litman et al showed that the rate of the first step of visual transduction (coupling of metarhodopsin II to the retinal G protein) was enhanced in DHA bilayers relative to less unsaturated phospholipids [14]. The same group went further by proving that the reduction of the phospholipid acyl chain unsaturation gives rise to a downregulation of individual steps in retinal G protein-coupled receptor pathways as illustrated by a reduced rhodopsin activation, a reduced rhodopsin-transducin coupling, a reduced cGMP phosphodiesterase activity, and a slower formation of the metarhodopsin II-G protein complex [15].…”