Modulation of metarhodopsin formation by cholesterol-induced ordering of bilayer lipids

Mitchell, Drake C.; Straume, Martin; Miller, James L.; Litman, Burton J.

doi:10.1021/bi00491a007

Cited by 210 publications

(147 citation statements)

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“…The equilibrium orientational distribution properties of DPH are summarized by the derived parameter f v . We have shown previously that K eq increases with increasing f v (16,18,30). In disk membranes, ethanol, butanol, and hexanol caused a concentration dependent increase in f v , while decanol induced a decrease in f v , Fig.…”

Section: Resultsmentioning

confidence: 66%

“…MII binds and activates the visual G protein, transducin (12, 13). MII formation increases with higher levels of phospholipid acyl chain unsaturation (14 -17) and decreasing levels of cholesterol (16,18).Differentiating between the two proposed mechanisms of action of alcohols and general anesthetics is difficult. However, studying the lipid dependence of the dose-response behavior of receptors in reconstituted systems is an explicit way of determining the lipid involvement in the action of these molecules.…”

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confidence: 99%

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Primary Alcohols Modulate the Activation of the G Protein-coupled Receptor Rhodopsin by a Lipid-mediated Mechanism

Mitchell

Lawrence

Litman

1996

Journal of Biological Chemistry

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The visual pigment rhodopsin is a prototypical member of the G protein-coupled receptor superfamily. In this study, we have investigated the effect of a series of n-alcohols on the formation of metarhodopsin II (MII), the photoactivated conformation of rhodopsin, which binds and activates transducin. When rhodopsin was photolyzed in the presence of several n-alcohols, increased MII formation was observed in the order ethanol > butanol > hexanol, whereas longer chain n-alcohols inhibited MII formation with decanol > octanol. The magnitude of the stimulatory effects was greater in a more highly unsaturated phospholipid. Alcohols, which enhanced MII formation also increased phospholipid acyl chain packing free volume, while those that decreased this bilayer property inhibited MII formation. An apparent discontinuity in the effect of these alcohols results when their potency is calculated in terms of the total aqueous alcohol concentration. In sharp contrast, a continuous variation in their behavior is observed, when their potency is calculated in terms of the amount of alcohol partitioned in the membrane. Our findings strongly support a lipid-mediated mechanism of action for alcohols on rhodopsin and, by analogy, for other G protein-coupled receptors.The mechanism of action of alcohols and general anesthetics is generally discussed in terms of two opposing mechanisms. The first involves an alteration of phospholipid bilayer properties by these agents, resulting in a modulation of membrane protein function, while the second is based on the direct interaction with membrane proteins (1, 2). The lipid mechanism was based originally on the observation (3, 4) that anesthetic potency correlated directly with the solubility of an anesthetic in olive oil. Additional support for the lipid mechanism came from the observation that acute exposure of membranes to ethanol resulted in a disordering of the phospholipid acyl chain packing (5). Subsequent experiments demonstrating that the activity of a soluble enzyme, firefly luciferase, could be inhibited by a diverse group of alcohols and general anesthetics (6) have focused attention on the protein binding hypothesis.Many of the recent studies aimed at elucidating the mechanism of action of alcohols and general anesthetics have dealt with the effect of these agents on ligand-gated channels, whose ligand binding site is in a portion of the protein external to the bilayer (1, 7-10). The superfamily of G protein-coupled receptors has received relatively little study. In these receptors, the ligand binding sites are formed by their transmembrane helical segments and lie at the median point of the bilayer. One of the best characterized members of this superfamily is rhodopsin, which triggers the visual transduction pathway in rod cells. A metastable equilibrium between MI 1 and MII (whereis established within milliseconds of photon absorption (11). MII binds and activates the visual G protein, transducin (12, 13). MII formation increases with higher levels of phospholipid acyl chain u...

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Section: Resultsmentioning

confidence: 66%

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Primary Alcohols Modulate the Activation of the G Protein-coupled Receptor Rhodopsin by a Lipid-mediated Mechanism

Mitchell

Lawrence

Litman

1996

Journal of Biological Chemistry

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“…Their studies demonstrated that systematic changes in the cholesterol composition of reconstituted phosphatidylcholinerhodopsin vesicles has profound changes on the formation of R*. These changes correspond to changes in the dynamics of the bilayer hydrocarbon region [67][68][69][70][71]. These studies indicate that cholesterol can exert an effect on rhodopsin function by reducing the partial free volume in the hydrocarbon core of the bilayer.…”

Section: Cholesterol and Rhodopsin Function In Reconstituted Rhodopsimentioning

confidence: 97%

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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“…It was frequently reported to regulate GPCR signaling (Oates and Watts, 2011). The effect of cholesterol on the order and fluidity of the membrane may be an important parameter for receptor function (Mitchell et al, 1990), but direct cholesterol-receptor interactions have also been described (Albert et al, 1996). Remarkably, the effect of cholesterol on GPCR function is receptor dependent.…”

Section: Rm and Hmnsmentioning

confidence: 99%

G protein-coupled receptor-receptor interactions give integrative dynamics to intercellular communication

Guidolin

Marcoli

Tortorella

et al. 2018

Reviews in the Neurosciences

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Abstract:The proposal of receptor-receptor interactions (RRIs) in the early 1980s broadened the view on the role of G protein-coupled receptors (GPCR) in the dynamics of the intercellular communication. RRIs, indeed, allow GPCR to operate not only as monomers but also as receptor complexes, in which the integration of the incoming signals depends on the number, spatial arrangement, and order of activation of the protomers forming the complex. The main biochemical mechanisms controlling the functional interplay of GPCR in the receptor complexes are direct allosteric interactions between protomer domains. The formation of these macromolecular assemblies has several physiologic implications in terms of the modulation of the signaling pathways and interaction with other membrane proteins. It also impacts on the emerging field of connectomics, as it contributes to set and tune the synaptic strength. Furthermore, recent evidence suggests that the transfer of GPCR and GPCR complexes between cells via the exosome pathway could enable the target cells to recognize/decode transmitters and/or modulators for which they did not express the pertinent receptors. Thus, this process may also open the possibility of a new type of redeployment of neural circuits. The fundamental aspects of GPCR complex formation and function are the focus of the present review article.

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Modulation of metarhodopsin formation by cholesterol-induced ordering of bilayer lipids

Cited by 210 publications

References 20 publications

Primary Alcohols Modulate the Activation of the G Protein-coupled Receptor Rhodopsin by a Lipid-mediated Mechanism

Primary Alcohols Modulate the Activation of the G Protein-coupled Receptor Rhodopsin by a Lipid-mediated Mechanism

The role of cholesterol in rod outer segment membranes

G protein-coupled receptor-receptor interactions give integrative dynamics to intercellular communication

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