Reduced G Protein-coupled Signaling Efficiency in Retinal Rod Outer Segments in Response to n-3 Fatty Acid Deficiency

Abstract

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 ϳ80% 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, rhodopsintransducin (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.

Docosahexaenoic acid: A positive modulator of Akt signaling in neuronal survival

“…Docosahexaenoic acid (DHA, 22:6, n-3), a long-chain n-3 polyunsaturated fatty acid, is highly enriched in the nervous system (5). Inadequate supply of n-3 fatty acids during prenatal and postnatal development decreases the levels of DHA in neuronal tissues with a reciprocal increase of docosapentaenoic acid (DPA, 22:5 n-6) (6), leading to a variety of visual, cognitive, and͞or behavioral deficits in animal models (7)(8)(9). Conversely, dietary supply of DHA during infancy has been shown to improve mental development in humans (10,11).…”

Human milk: maternal dietary lipids and infant development

“…DHA comprises £ 80 % of the PUFA in the retina outer segment disks, and phospholipids are present in which both fatty acids are DHA. In vitro studies have provided evidence that DHA plays a role in photoreceptor signal transduction by influencing the ability of photons to transform rhodopsin to the activated meta-rhodopsin ll state and the efficiency of G-protein-coupled receptor signalling (Niu et al 2004). More recently, it has been shown (Soubias et al 2006) that there are specific binding sites for DHA in the rhodopsin molecules.…”

The impact of long-chainn-3 polyunsaturated fatty acids on human health

“…Studies of mammalian retina revealed that DHA accounts for half of the total fatty acid content in the retina (Stinson et al 1991). The functional importance of DHA may be related to the interaction of the photoactive protein rhodopsin with DHAcontaining phospholipids (Gordon & Bazan, 1990;Niu et al 2004). Phospholipid bilayers rich in DHA have a high fluidity and enhanced rates of fusion and permeability which are characteristics vital to the normal functioning of photoreceptor cells (Giusto et al 2000).…”