Partial Agonist Activity of 11-cis-Retinal in Rhodopsin Mutants

Han, May; Lou, Jihong; Nakanishi, Koji; Sakmar, Thomas P.; Smith, Steven O.

doi:10.1074/jbc.272.37.23081

Cited by 42 publications

(32 citation statements)

References 32 publications

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“…Thus, structural changes in the region near Glu 122 and His 211 are required for proper repositioning of the ␤-ionone ring (27). Previous studies have show a direct interaction between 11-cis-retinal and Gly 121 in rhodopsin TM III (31)(32)(33)(34)(35). The increase in the size of Gly 121 correlated directly with the increasing dark state activity.…”

Section: Discussionmentioning

confidence: 84%

Critical Role of Transmembrane Segment Zinc Binding in the Structure and Function of Rhodopsin

Stojanović

Stitham

Hwa

2004

Journal of Biological Chemistry

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Zinc deficiency and retinitis pigmentosa are both important factors resulting in retinal dysfunction and night blindness. In this study, we address the critical biochemical and structural relevance of zinc ions in rhodopsin and examine whether zinc deficiency can lead to rhodopsin dysfunction. We report the identification of a high-affinity zinc coordination site within the transmembrane domain of rhodopsin, coordinated by the side chains of two highly conserved residues, Glu 122 in transmembrane helix III and His 211 in transmembrane helix V. We also demonstrate that this zinc coordination is critical for rhodopsin folding, 11-cis-retinal binding, and the stability of the chromophore-receptor interaction, defects of which are observed in retinitis pigmentosa. Furthermore, a cluster of retinitis pigmentosa mutations is localized within and around this zinc binding site. Based on these studies, we believe that improvement in zinc binding to rhodopsin at this site within the transmembrane domain may be a pharmacological approach for the treatment of select retinitis pigmentosa mutations. Transmembrane coordination of zinc may also be an important common principle across G-protein-coupled receptors.Several neurodegenerative disorders, Alzheimer disease, Parkinson disease, familial amyotrophic lateral sclerosis, and the transmissible spongiform encephalopathies, share a common pathogenesis involving the misfolding and aggregation of specific proteins. Mounting evidence has demonstrated the direct binding of zinc (Zn 2ϩ ) to the ␤-amyloid (Alzheimer disease), ␣-synuclein (Parkinson disease), superoxide dismutase (amyotrophic lateral sclerosis), and prion (transmissible spongiform encephalopathies) proteins, linking either the gain or loss of Zn 2ϩ binding to the progression of these severe protein misfolding disorders. Zn 2ϩ promotes aggregation of the highly fibrillogenic prion peptide, PrP106 -126 (1), and of the ␤-amyloid protein (2-4) into amyloidogenic aggregates. Clioquinol, a metal chelating agent, is currently being investigated as a potential therapeutic solution to inhibit ␤-amyloid neurotoxicity (5). In contrast, in mutant superoxide dismutase protein, loss of affinity for Zn 2ϩ results in diminished protein activity (6), reduced protein stability (7), and formation of amyloid-like filaments (8). Thus, both zinc deficiencies and excesses can lead to neurodegenerative diseases.In the G protein-coupled photoreceptor rhodopsin, there have been over 100 distinct, heritable mutations identified, many of which induce an altered protein conformation, misfolding, aggregation, and cell death, followed by the clinical manifestation of the retinal neurodegenerative disorder retinitis pigmentosa (9). Interestingly, Zn 2ϩ deficiency is also known to cause retinal neurodegeneration and night blindness (10), symptoms reminiscent of retinitis pigmentosa. Furthermore, Zn 2ϩ has been shown to directly bind rhodopsin (11,12) and to reduce rhodopsin thermal stability and regeneration with 11-cis-retinal at higher Zn 2ϩ concen...

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Section: Discussionmentioning

confidence: 84%

Critical Role of Transmembrane Segment Zinc Binding in the Structure and Function of Rhodopsin

Stojanović

Stitham

Hwa

2004

Journal of Biological Chemistry

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“…The resulting fatty acid amides of Ret-NH 2 other inhibitors of the visual cycle (18)(19)(20). 11-cis-Retinal acts as an opsin inverse agonist (23). Therefore, suppression of 11-cis-retinal production by visual cycle inhibitors gives rise to unliganded, constitutively active opsins that initiate low-level activation of the phototransduction cascade (ref.…”

Section: Inhibitory Effects Of Ret-nhmentioning

confidence: 99%

Molecular pharmacodynamics of emixustat in protection against retinal degeneration

Zhang

Kiser²,

Badiee

et al. 2015

J. Clin. Invest.

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“…The inverse agonist 11-cisretinal behaves as a partial agonist at the Gly 121 Leu mutation in transmembrane domain III of rhodopsin (Han et al, 1997). The single amino acid substitution Asp 113 Glu in the third transmembrane domain of the hamster b 2 AR promotes partial agonist activity for pindolol, oxyprenolol and alprenolol, ligands that act as antagonists at the wt b 2 AR (Strader et al, 1989).…”

Section: Partial Agonist Activity Of Antagonists At Mutant G-protein-mentioning

confidence: 99%

G‐protein activation by putative antagonists at mutant Thr³⁷³Lys α_2A adrenergic receptors

Wurch

Colpaert

Pauwels

1999

British J Pharmacology

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1 Replacement of a threonine by a lysine at position 373 in the C-terminal portion of the third intracellular loop of the human a 2A -adrenergic receptor (a 2A AR) has been reported to generate a constitutively active mutant receptor in analogy with similar mutations in the a 1B and b 2 AR (Ren et al., 1993). In the present study, the mutant Thr 373 Lys a 2A AR receptor was investigated by measuring the formation of inositol phosphates in either the absence or presence of mouse G a15 protein in Cos-7 cells. 2 Increased a nity, potency and/or e cacy for the agonists [(7)-adrenaline, UK 14304, clonidine, guanabenz and oxymetazoline] was observed, consistent with a precoupled mutant a 2A AR: Gprotein state. The basal inositol phosphates response was similar at the wild-type (wt) and mutant a 2A AR, but was enhanced at the mutant a 2A AR upon co-expression with the mouse G a15 protein.This enhanced response could not be attenuated in the presence of any of the tested a 2 AR antagonists (10 mM), suggesting that inverse agonist activity did not occur at the mutant a 2A AR. 4 The partial agonist e ect of SKF 86466 was resistant to pertussis toxin treatment (100 ng ml 71 ) and not a ected by co-expression of the rat G ai1 protein. It was virtually absent in the presence of 10 mM RS 15385. SKF 86466 was without intrinsic activity upon co-expression of the mouse G aq protein.5 Some putative a 2 AR antagonists exerted a partial agonist activity that was highly dependent on the presence of speci®c G-protein a-subunits, suggesting that these ligands cause selective G-protein activation at the mutant a 2A AR.

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Partial Agonist Activity of 11-cis-Retinal in Rhodopsin Mutants

Cited by 42 publications

References 32 publications

Critical Role of Transmembrane Segment Zinc Binding in the Structure and Function of Rhodopsin

Critical Role of Transmembrane Segment Zinc Binding in the Structure and Function of Rhodopsin

Molecular pharmacodynamics of emixustat in protection against retinal degeneration

G‐protein activation by putative antagonists at mutant Thr³⁷³Lys α_2A adrenergic receptors

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Partial Agonist Activity of 11-cis-Retinal in Rhodopsin Mutants

Cited by 42 publications

References 32 publications

Critical Role of Transmembrane Segment Zinc Binding in the Structure and Function of Rhodopsin

Critical Role of Transmembrane Segment Zinc Binding in the Structure and Function of Rhodopsin

Molecular pharmacodynamics of emixustat in protection against retinal degeneration

G‐protein activation by putative antagonists at mutant Thr373Lys α2A adrenergic receptors

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G‐protein activation by putative antagonists at mutant Thr³⁷³Lys α_2A adrenergic receptors