Highly polyunsaturated phospholipids produce membranes with several unique characteristics, and these characteristics are beneficial to many biological membrane functions. The high levels of 22:6n-3 acyl chains in the membrane phospholipids of the nervous system and retina suggest that these phospholipids play an important structural role. There is general agreement that the presence of polyunsaturated acyl chains in the phospholipids of membranes imparts a variety of unique features to these membranes. The specialized physical properties of highly polyunsaturated bilayers include increased bilayer area per headgroup, increased water permeability, higher degree of acyl chain flexibility, dynamics and disorder, sharply reduced interaction with cholesterol, and a tendency to enhance the formation of lateral domains. Although the actual forces that modulate protein function are still under investigation, it is clear that the unique properties imparted to biological membranes by the presence of polyunsaturated acyl chains and, in particular, 22:6n-3 chains play a fundamental role in determining membrane protein function.

The visual pathway, which is a prototypical G-protein-coupled receptor system, is one of the best characterized of this family of receptor systems. Various steps in this pathway are optimized in 22:6n-3-containing bilayers. The highest levels of MII formation in reconstituted systems are observed in 22:6n-3-containing bilayers (Litman & Mitchell, 1996b). The 22:6n-3-containing bilayers exhibited increased levels of MII-Gt complex formation and more favorable kinetic coupling of MII and Gt, relative to less unsaturated membrane systems (Litman et al., 2001). MII and Gt must interact rapidly to form a complex upon formation of MII in order to make signaling along the pathway efficient. As the bilayer acyl chains become less unsaturated, this process becomes delayed, introducing a lag time in the signaling process. Reduced affinity of the receptor, MII, for Gt will result in less amplification in the pathway, resulting from there being fewer Gts activated. Observations made in reconstituted systems are in good agreement with elec-troretinogram (ERG) measurements made on n-3-deficient animals, where reduced signal amplitude and a lag time in signal development are seen. In view of the similarities between the visual system and other G-protein-coupled receptor pathways, the findings in the vision pathway ought to be applicable to neurotransmitter receptors in this super-family. This extrapolation is supported by studies evaluating olfactory discrimination of rats raised on either an n-3-deficient or n-3-adequate diet. The n-3-adequate group made fewer errors in odor discrimination tests than the n-3-deficient group (Greiner et al, 1999). The olfactory bulb of rats raised on an n-3-deficient diet showed an 82% loss of 22:6n-3 relative to rats raised on an n-3-adequate diet. Olfactory and visual signaling are both G-protein-coupled receptor pathways and both are less sensitive in 22:6n-3-deficient animals.

The finding that 22:6n-3-containing bilayers buffer the inhibitory effects of cholesterol has strong implications for psychological disorders that are associated with variable levels of cholesterol. Under conditions of reduced levels of 22:6n-3 in n-3-deficiency and an increased cholesterol level, a reduced sensitivity in G-protein-coupled receptor signaling would be anticipated. Thus, the effectiveness of serotonin or other associated neu-rotransmitters would be decreased, potentially inducing some of the observed psychological dysfunction associated with cholesterol.

The studies described herein provide insight into the mechanism whereby 22:6n-3-containing phospholipids optimize membrane-associated signaling processes. Studies of both odor discrimination in n-3-deficient rats (Greiner et al, 1999) and visual deficits in n-3-deficient rhesus monkeys (Neuringer et al., 1984) and formula-fed infants (Birch et al., 2000) demonstrate a marked desensitization of two distinct G-protein-coupled signaling pathways to 22:6n-3 deficiency. It is anticipated that the sensitivity of G-protein-coupled receptor systems to levels of 22:6n-3 in membrane phospholipids will be of a general nature and this phenomenon may provide an explanation of the deficiencies in cognitive processes observed in n-3 deficiency.

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