The asymmetric transmembrane distribution of phosphatidylethanolamine, phosphatidylserine, and fatty acids of the bovine retinal rod outer segment disk membrane

Miljanich, George P.; Nemes, Péter; White, D. L.; Dratz, Edward A.

doi:10.1007/bf01992562

Cited by 88 publications

(53 citation statements)

References 20 publications

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“…Typically, for plasma membranes PC is high in the extracellular monolayer while PE and PS are high in the intracellular monolayer. In the case of disk membrane lipids PE is preferentially, although not exclusively located on the extradiskal surface and PC is preferentially located on the intradiskal surface [85,86]. This is consistent with the disk origin as an evagination of the plasma membrane.…”

Section: Organization Of Cholesterol In Disk Membranessupporting

confidence: 78%

The role of cholesterol in rod outer segment membranes

Albert

Boesze‐Battaglia

2005

Progress in Lipid Research

112

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The photoreceptor rod outer segment (ROS) provides a unique system in which to investigate the role of cholesterol, an essential membrane constituent of most animal cells. The ROS is responsible for the initial events of vision at low light levels. It consists of a stack of disk membranes surrounded by the plasma membrane. Light capture occurs in the outer segment disk membranes that contain the photopigment, rhodopsin. These membranes originate from evaginations of the plasma membrane at the base of the outer segment. The new disks separate from the plasma membrane and progressively move up the length of the ROS over the course of several days. Thus the role of cholesterol can be evlauated in two distinct membranes. Furthermore, because the disk membranes vary in age it can also be investigated in a membrane as a function of the membrane age. The plasma membrane is enriched in cholesterol and in saturated fatty acids species relative to the disk membrane. The newly formed disk membranes have 6-fold more cholesterol than disks at the apical tip of the ROS. The partitioning of cholesterol out of disk membranes as they age and are apically displaced is consistent with the high PE content of disk membranes relative to the plasma membrane. The cholesterol composition of membranes has profound consequences on the major protein, rhodopsin. Biophysical studies in both model membranes and in native membranes have demonstrated that cholesterol can modulate the activity of rhodopsin by altering the membrane hydrocarbon environment. These studies suggest that mature disk membranes initiate the visual signal cascade more effectively than the newly synthesized, high cholesterol basal disks. Although rhodopsin is also the major protein of the plasma membrane, the high membrane cholesterol content inhibits rhodopsin participation in the visual transduction cascade. In addition to its effect on the hydrocarbon region, cholesterol may interact directly with rhodopsin. While high cholesterol inhibits rhodopsin activation, it also stabilizes the protein to denaturation. Therefore the disk membrane must perform a balancing act providing sufficient cholestrol to confer stability but without making the membrane too restrictive to receptor activation. Within a given disk membrane, it is likely that cholesterol exhibits an asymmetric distribution between the inner and outer bilayer leaflets. Furthremore, there is some evidence of cholesterol microdomains in the disk membranes. The availability of the disk protein, rom-1 may be sensitive to membrane cholesterol. The effects exerted by cholesterol on rhodopsin function have far-reaching implications for the study of G-protein coupled receptors as a whole. These studies show that the function of a membrane receptor can be modulated by modification of HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript the lipid bilayer, particularly cholesterol. This provides a powerful means of fine-tuning the activity of a membrane protein without resorting ...

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Section: Organization Of Cholesterol In Disk Membranessupporting

confidence: 78%

The role of cholesterol in rod outer segment membranes

Albert

Boesze‐Battaglia

2005

Progress in Lipid Research

112

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“…A number of earlier studies have focused on phospholipid asymmetry in bovine photoreceptor disc membranes. Although initial reports suggested that disc membranes were highly asymmetrical with respect to the transbilayer distribution of PS and PE in disc membranes (Miljanich et al, 1981;Wu and Hubbell, 1993), subsequent studies have indicated that PC and PE are symmetrically distributed across the bilayer with PS exhibiting an ATP-independent asymmetrical distribution resulting from the high density and orientation of rhodopsin (Hessel et al, 2000;Wu and Hubbell, 1993). The recently reported scramblase activity of rhodopsin (Menon et al, 2011) might overwhelm the ATP-dependent phospholipid flippase activity of ATP8A2, resulting in a random distribution of phospholipids across the disc membrane.…”

Section: Discussionmentioning

confidence: 97%

Phospholipid flippase ATP8A2 is required for normal visual and auditory function and photoreceptor and spiral ganglion cell survival

Coleman

Zhu

Djajadi

et al. 2014

Journal of Cell Science

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ATP8A2 is a P 4 -ATPase that is highly expressed in the retina, brain, spinal cord and testes. In the retina, ATP8A2 is localized in photoreceptors where it uses ATP to transport phosphatidylserine (PS) and phosphatidylethanolamine (PE) from the exoplasmic to the cytoplasmic leaflet of membranes. Although mutations in ATP8A2 have been reported to cause mental retardation in humans and degeneration of spinal motor neurons in mice, the role of ATP8A2 in sensory systems has not been investigated. We have analyzed the retina and cochlea of ATP8A2-deficient mice to determine the role of ATP8A2 in visual and auditory systems. ATP8A2-deficient mice have shortened photoreceptor outer segments, a reduction in photoresponses and decreased photoreceptor viability. The ultrastructure and phagocytosis of the photoreceptor outer segment appeared normal, but the PS and PE compositions were altered and the rhodopsin content was decreased. The auditory brainstem response threshold was significantly higher and degeneration of spiral ganglion cells was apparent. Our studies indicate that ATP8A2 plays a crucial role in photoreceptor and spiral ganglion cell function and survival by maintaining phospholipid composition and contributing to vesicle trafficking.

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“…It has been proposed that the cytoplasmic face of rhodopsin is positively charged (23) with a net charge of +4 to +6 (24). Phosphatidylserine is the only quantitatively significant lipid with a net charge, and evidence has been presented that 8-10 phosphatidylserines per rhodopsin are on the cytoplasmic membrane surface (25). The phosphatidylserine would contribute a negative charge of -8 to -10 to the cytoplasmic membrane surface per rhodopsin.…”

Section: Discussionmentioning

confidence: 99%

Sensitive light scattering probe of enzymatic processes in retinal rod photoreceptor membranes

Lewis

Miller

Mendel-Hartvig

et al. 1984

Proc. Natl. Acad. Sci. U.S.A.

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Light excitation of as little as 0.05% of the rhodopsin in a retinal rod membrane suspension reduces the near-IR optical transmission by 25%. This transmission decrease requires the presence of guanosine triphosphate, is opposite in sign and 25 times larger in amplitude than a GTPdependent light-scattering signal previously reported in rod outer segment suspensions [Kuhn, H., Bennett, N., MichelVallez, M. & Chabre, M. (1981) Proc. Natl. Acad. Sci. USA, 78,[6873][6874][6875][6876][6877], and is kinetically complex. The initial phase of the optical transmission decrease begins after about a 50-ms lag (at 0.05% bleach) and has a first-order time constant of 300-500 ms. The scattering signal returns to the preactinic baseline in a time dependent on the amount of GTP added. A nonhydrolyzable GTP analogue, guanylyl imidodiphosphate, produces a scattering signal that does not return to the preactinic baseline. Adenosine triphosphate strongly inhibits the return of the GTP-dependent transmission decrease to the preactinic baseline. This effect of ATP on the GTP signal apparently requires ATP hydrolysis because it is inhibited by the simultaneous presence of adenylyl imidodiphosphate, a nonhydrolyzable analogue of ATP. The light-scattering signal and the velocity of the activation of a rod outer segment phosphodiesterase saturate when >0.05% of the rhodopsin is bleached and both show nearly identical dependence on light stimulus. It is suggested that these nucleotide-dependent light-scattering signals arise from changes in the state of membrane aggregation that are controlled by enzymatic processes. This hypothesis is supported by the large amplitude of the signals, sedimentation experiments, and a strong membrane concentration dependence. The ATP effects can be rationalized within the above hypothesis as being due to ATP-dependent rhodopsin phosphorylation that adds negative charges to the membrane surface and tends to keep the membranes disaggregated. An additional signal, which increases light transmission, is produced by a second, much more intense flash. The latter signal is interpreted as the result of proton binding by bleached rhodopsin molecules that decreases the negative charge repulsion between the membranes and allows increased aggregation.Retinal rod outer segments (ROS) contain several proteins, other than the visual pigment rhodopsin, whose activities are modulated by light (1)(2)(3)(4). The fact that these proteins are light activated makes it likely that they participate in the process of visual transduction or light adaptation. It is clear that an active form of bleached rhodopsin, R*, catalyzes the binding of GTP to a GTP-binding protein (3, 5-7). Once GTP is bound, the binding protein then activates a phosphodiesterase (PDE) until the bound GTP is hydrolyzed (1,8). R* catalyzes the binding of GTP to a large number of GTP-binding protein molecules until it is inactivated by either slow thermal processes or faster phosphorylation by rhodopsin kinase (ref. 9; unpublished data). Kuhn et al. (10...

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The asymmetric transmembrane distribution of phosphatidylethanolamine, phosphatidylserine, and fatty acids of the bovine retinal rod outer segment disk membrane

Cited by 88 publications

References 20 publications

The role of cholesterol in rod outer segment membranes

The role of cholesterol in rod outer segment membranes

Phospholipid flippase ATP8A2 is required for normal visual and auditory function and photoreceptor and spiral ganglion cell survival

Sensitive light scattering probe of enzymatic processes in retinal rod photoreceptor membranes

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