Chromophore Of Visual Pigments Research Articles

Unraveling the mystery of ocular retinoid turnover: Insights from albino mice and the role of STRA6

A delicate balance between photon absorption for vision and protection of photoreceptors from light damage is pivotal for ocular health. This equilibrium is governed by the light-absorbing 11-cis-retinylidene chromophore of visual pigments, which, upon bleaching, transforms into all-trans-retinal and undergoes regeneration through an enzymatic pathway, named the visual cycle. Chemical side reactions of retinaldehydes during the recycling process can generate byproducts that may result in a depletion of retinoids. In our study, we have clarified the crucial roles played by melanin pigmentation and the retinoid transporter STRA6 in preventing this loss and preserving the integrity of the visual cycle. Our experiments initially confirmed that consecutive green and blue light bleaching of isolated bovine rhodopsin produced 9-cis and 13-cis retinal. The same unusual retinoids were found in the retinas of mice exposed to intense light, with elevated concentrations observed in albino mice. Examining the metabolic fate of these visual cycle byproducts revealed that 9-cis-retinal, but not 13-cis-retinal, was recycled back to all-trans-retinal through an intermediate called isorhodopsin. However, investigations in Stra6 knockout mice unveiled that the generation of these visual cycle byproducts correlated with a light-induced loss of ocular retinoids and visual impairment. Collectively, our findings uncover important novel aspects of visual cycle dynamics, with implications for ocular health and photoreceptor integrity.

Ligand-based rational design, synthesis and evaluation of novel potential chemical chaperones for opsin

Inherited blinding diseases retinitis pigmentosa (RP) and a subset of Leber's congenital amaurosis (LCA) are caused by the misfolding and mistrafficking of rhodopsin molecules, which aggregate and accumulate in the endoplasmic reticulum (ER), leading to photoreceptor cell death. One potential therapeutic strategy to prevent the loss of photoreceptors in these conditions is to identify opsin-binding compounds that act as chemical chaperones for opsin, aiding its proper folding and trafficking to the outer cell membrane. Aiming to identify novel compounds with such effect, a rational ligand-based approach was applied to the structure of the visual pigment chromophore, 11-cis-retinal, and its locked analogue 11-cis-6mr-retinal. Following molecular docking studies on the main chromophore binding site of rhodopsin, 49 novel compounds were synthesized according to optimized one-to seven-step synthetic routes. These agents were evaluated for their ability to compete for the chromophore binding site of opsin, and their capacity to increase the trafficking of the P23H opsin mutant from the ER to the cell membrane. Different new molecules displayed an effect in at least one assay, acting either as chemical chaperones or as stabilizers of the 9-cis-retinal-rhodopsin complex. These compounds could provide the basis to develop novel therapeutics for RP and LCA.

Computational Studies towards the Identification of Novel Rhodopsin-Binding Compounds as Chemical Chaperones for Misfolded Opsins.

Accumulation of misfolded and mistrafficked rhodopsin on the endoplasmic reticulum of photoreceptor cells has a pivotal role in the pathogenesis of retinitis pigmentosa and a subset of Leber’s congenital amaurosis. One potential strategy to reduce rhodopsin misfolding and aggregation in these conditions is to use opsin-binding compounds as chemical chaperones for opsin. Such molecules have previously shown the ability to aid rhodopsin folding and proper trafficking to the outer cell membranes of photoreceptors. As means to identify novel chemical chaperones for rhodopsin, a structure-based virtual screening of commercially available drug-like compounds (300,000) was performed on the main binding site of the visual pigment chromophore, the 11-cis-retinal. The best 24 virtual hits were examined for their ability to compete for the chromophore-binding site of opsin. Among these, four small molecules demonstrated the ability to reduce the rate constant for the formation of the 9-cis-retinal-rhodopsin complex, while five molecules surprisingly enhanced the formation of this complex. Compound 7, 13, 20 and 23 showed a weak but detectable increase in the trafficking of the P23H mutant, widely used as a model for both retinitis pigmentosa and Leber’s congenital amaurosis, from the ER to the cell membrane. The compounds did not show any relevant cytotoxicity in two different human cell lines, with the only exception of 13. Based on the structures of these active compounds, a series of in silico studies gave important insights on the potential structural features required for a molecule to act either as chemical chaperone or as stabiliser of the 11-cis-retinal-rhodopsin complex. Thus, this study revealed a series of small molecules that represent a solid foundation for the future development of novel therapeutics against these severe inherited blinding diseases.

The Single Administration of a Chromophore Alleviates Neural Defects in Diabetic Retinopathy

Diabetic retinopathy (DR) is a common complication of diabetes and a leading cause of blindness among the working-age population. Diabetic patients often experience functional deficits in dark adaptation, contrast sensitivity, and color perception before any microvascular pathologies on the fundus become detectable. Previous studies showed that the regeneration of 11-cis-retinal and visual pigment is impaired in a type 1 diabetes animal model, which negatively affects visual function at the early stage of DR. Here, Akita mice, type 1 diabetic model, were treated with the visual pigment chromophore, 9-cis-retinal. This treatment rescued a- and b-wave amplitudes of scotopic electroretinography responses, compared with vehicle-treated Akita mice. In addition, the administration of 9-cis-retinal alleviated oxidative stress significantly as shown by reduced 3-nitrotyrosine levels in the retina of Akita mice. Furthermore, the 9-cis-retinal treatment decreased retinal apoptosis as shown by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and DNA fragment enzyme-linked immunosorbent assay. Overall, these findings showed that 9-cis-retinal administration restored visual pigment formation and decreased oxidative stress and retinal degeneration, which resulted in improved visual function in diabetic mice, suggesting that chromophore deficiency plays a causative role in visual defects in early DR.

Photic generation of 11-cis-retinal in bovine retinal pigment epithelium

Photoisomerization of the 11-cis-retinal chromophore of rod and cone visual pigments to an all-trans-configuration is the initiating event for vision in vertebrates. The regeneration of 11-cis-retinal, necessary for sustained visual function, is an endergonic process normally conducted by specialized enzyme systems. However, 11-cis-retinal also can be formed through reverse photoisomerization from all-trans-retinal. A nonvisual opsin known as retinal pigment epithelium (RPE)-retinal G-protein-coupled receptor (RGR) was previously shown to mediate visual chromophore regeneration in photic conditions, but conflicting results have cast doubt on its role as a photoisomerase. Here, we describe high-level production of 11-cis-retinal from RPE membranes stimulated by illumination at a narrow band of wavelengths. This activity was associated with RGR and enhanced by cellular retinaldehyde-binding protein (CRALBP), which binds the 11-cis-retinal produced by RGR and prevents its re-isomerization to all-trans-retinal. The activity was recapitulated with cells heterologously expressing RGR and with purified recombinant RGR. Using an RGR variant, K255A, we confirmed that a Schiff base linkage at Lys-255 is critical for substrate binding and isomerization. Single-cell RNA-Seq analysis of the retina and RPE tissue confirmed that RGR is expressed in human and bovine RPE and Müller glia, whereas mouse RGR is expressed in RPE but not in Müller glia. These results provide key insights into the mechanisms of physiological retinoid photoisomerization and suggest a novel mechanism by which RGR, in concert with CRALBP, regenerates the visual chromophore in the RPE under sustained light conditions.

Two-State, Three-Mode Parametrization of the Force Field of a Retinal Chromophore Model.

In recent years, the potential energy surfaces of the penta-2,4-dieniminium cation have been investigated using several electronic structure methods. The resulting pool of geometrical, electronic, and energy data provides a suitable basis for the construction of a topographically correct analytical model of the molecule force field and, therefore, for a better understanding of this class of molecules, which includes the chromophore of visual pigments. In the present contribution, we report the construction of such a model for regions of the force field that drive the photochemical and thermal isomerization of the central double bound of the cation. While previous models included only two modes, it is here shown that the proposed three-mode model and corresponding set of parameters are able to reproduce the complex topographical and electronic structure features seen in electronically correlated data obtained at the XMCQDPT2//CASSCF/6-31G* level of theory.

Structural biology of 11-cis-retinaldehyde production in the classical visual cycle.

The vitamin A derivative 11-cis-retinaldehyde plays a pivotal role in vertebrate vision by serving as the chromophore of rod and cone visual pigments. In the initial step of vision, a photon is absorbed by this chromophore resulting in its isomerization to an all-trans state and consequent activation of the visual pigment and phototransduction cascade. Spent chromophore is released from the pigments through hydrolysis. Subsequent photon detection requires the delivery of regenerated 11-cis-retinaldehyde to the visual pigment. This trans-cis conversion is achieved through a process known as the visual cycle. In this review, we will discuss the enzymes, binding proteins and transporters that enable the visual pigment renewal process with a focus on advances made during the past decade in our understanding of their structural biology.

Peropsin modulates transit of vitamin A from retina to retinal pigment epithelium

Peropsin is a non-visual opsin in both vertebrate and invertebrate species. In mammals, peropsin is present in the apical microvilli of retinal pigment epithelial (RPE) cells. These structures interdigitate with the outer segments of rod and cone photoreceptor cells. RPE cells play critical roles in the maintenance of photoreceptors, including the recycling of visual chromophore for the opsin visual pigments. Here, we sought to identify the function of peropsin in the mouse eye. To this end, we generated mice with a null mutation in the peropsin gene (Rrh). These mice exhibited normal retinal histology, normal morphology of outer segments and RPE cells, and no evidence of photoreceptor degeneration. Biochemically, Rrh-/- mice had ∼2-fold higher vitamin A (all-trans-retinol (all-trans-ROL)) in the neural retina following a photobleach and 5-fold lower retinyl esters in the RPE. This phenotype was similar to those reported in mice that lack interphotoreceptor retinoid-binding protein (IRBP) or cellular retinol-binding protein, suggesting that peropsin plays a role in the movement of all-trans-ROL from photoreceptors to the RPE. We compared the phenotypes in mice lacking both peropsin and IRBP with those of mice lacking peropsin or IRBP alone and found that the retinoid phenotype was similarly severe in each of these knock-out mice. We conclude that peropsin controls all-trans-ROL movement from the retina to the RPE or may regulate all-trans-ROL storage within the RPE. We propose that peropsin affects light-dependent regulation of all-trans-ROL uptake from photoreceptors into RPE cells through an as yet undefined mechanism.

Impaired Rhodopsin Generation in the Rat Model of Diabetic Retinopathy

Diabetic retinopathy is a common complication of diabetes mellitus. Diabetic patients experience functional deficits in dark adaptation, contrast sensitivity, and color perception before microvascular pathologies become apparent. Herein, we evaluated early changes in neural retinal function and in retinoid metabolism in the eye in diabetes. Streptozotocin-induced diabetic rats showed decreased a- and b-wave amplitudes of scotopic and photopic electroretinography responses 4 months after diabetes induction compared to nondiabetic controls. Although Western blot analysis revealed no difference in opsin expression, rhodopsin content was decreased in diabetic retinas, as shown by a difference in absorbance. Consistently, levels of 11-cis-retinal, the chromophore for visual pigments, were significantly lower in diabetic retinas compared to those in controls, suggesting a retinoid deficiency. Among visual cycle proteins, interphotoreceptor retinoid-binding protein and stimulated by retinoic acid 6 protein showed significantly lower levels in diabetic rats than those in nondiabetic controls. Similarly, serum levels of retinol-binding protein 4 and retinoids were significantly lower in diabetic rats. Overall, these results suggest that retinoid metabolism in the eye is impaired in type 1 diabetes, which leads to deficient generation of visual pigments and neural retinal dysfunction in early diabetes.

Blue light regenerates functional visual pigments in mammals through a retinyl-phospholipid intermediate

The light absorbing chromophore in opsin visual pigments is the protonated Schiff base of 11-cis-retinaldehyde (11cRAL). Absorption of a photon isomerizes 11cRAL to all-trans-retinaldehyde (atRAL), briefly activating the pigment before it dissociates. Light sensitivity is restored when apo-opsin combines with another 11cRAL to form a new visual pigment. Conversion of atRAL to 11cRAL is carried out by enzyme pathways in neighboring cells. Here we show that blue (450-nm) light converts atRAL specifically to 11cRAL through a retinyl-phospholipid intermediate in photoreceptor membranes. The quantum efficiency of this photoconversion is similar to rhodopsin. Photoreceptor membranes synthesize 11cRAL chromophore faster under blue light than in darkness. Live mice regenerate rhodopsin more rapidly in blue light. Finally, whole retinas and isolated cone cells show increased photosensitivity following exposure to blue light. These results indicate that light contributes to visual-pigment renewal in mammalian rods and cones through a non-enzymatic process involving retinyl-phospholipids.

RPE65 and the Accumulation of Retinyl Esters in Mouse Retinal Pigment Epithelium.

The RPE65 protein of the retinal pigment epithelium (RPE) enables the conversion of retinyl esters to the visual pigment chromophore 11-cis retinal. Fresh 11-cis retinal is generated from retinyl esters following photoisomerization of the visual pigment chromophore to all-trans during light detection. Large amounts of esters accumulate in Rpe65-/- mice, indicating their continuous formation when 11-cis retinal generation is blocked. We hypothesized that absence of light, by limiting the conversion of esters to 11-cis retinal, would also result in the build-up of retinyl esters in the RPE of wild-type mice. We used HPLC to quantify ester levels in organic extracts of the RPE from wild-type and Rpe65-/- mice. Retinyl ester levels in Sv/129 wild-type mice that were dark adapted for various intervals over a 4-week period were similar to those in mice raised in cyclic light. In C57BL/6 mice however, which contain less Rpe65 protein, dark adaptation was accompanied by an increase in ester levels compared to cyclic light controls. Retinyl ester levels were much higher in Rpe65-/- mice compared to wild type and kept increasing with age. The results suggest that the RPE65 role in retinyl ester homeostasis extends beyond enabling the formation of 11-cis retinal.

錐体特異的な視物質再生過程での11-シス選択性

Vertebrate visual photoreceptor cells, rods and cones, consume 11-cis-retinal as a chromophore of visual pigment. 11-cis-retinal is supplied from two metabolic pathways; the retinal pigment epithelium pathway, which is common for both rods and cones, and the cone-specific intra retina pathway. The latter pathway is thought to support a rapid re-synthesis of 11-cis-retinal which is required for cone-mediated daylight vision. Recently, it was proposed that 9-cis-retinal, in addition to 11-cis isomer, is used in this cone-specific pathway and it might modulate sensitivity and spectral tuning of cone-mediated vision. This review summarizes our recent studies to test this hypothesis.

Structural Insights into the Drosophila melanogaster Retinol Dehydrogenase, a Member of the Short-Chain Dehydrogenase/Reductase Family.

The 11-cis-retinylidene chromophore of visual pigments isomerizes upon interaction with a photon, initiating a downstream cascade of signaling events that ultimately lead to visual perception. 11-cis-Retinylidene is regenerated through enzymatic transformations collectively called the visual cycle. The first and rate-limiting enzymatic reaction within this cycle, i.e., the reduction of all-trans-retinal to all-trans-retinol, is catalyzed by retinol dehydrogenases. Here, we determined the structure of Drosophila melanogaster photoreceptor retinol dehydrogenase (PDH) isoform C that belongs to the short-chain dehydrogenase/reductase (SDR) family. This is the first reported structure of a SDR that possesses this biologically important activity. Two crystal structures of the same enzyme grown under different conditions revealed a novel conformational change of the NAD+ cofactor, likely representing a change during catalysis. Amide hydrogen-deuterium exchange of PDH demonstrated changes in the structure of the enzyme upon dinucleotide binding. In D. melanogaster, loss of PDH activity leads to photoreceptor degeneration that can be partially rescued by transgenic expression of human RDH12. Based on the structure of PDH, we analyzed mutations causing Leber congenital amaurosis 13 in a homology model of human RDH12 to obtain insights into the molecular basis of RDH12 disease-causing mutations.

Cone Health and Retinoids.

Cones are photoreceptor cells used for bright light and color vision. Retinoids are vitamin A derivatives, one of which is the 11-cis aldehyde form that serves as the chromophore for both cone and rod visual pigments. In the visual disease, Type 2 Leber congenital amaurosis (LCA2), 11-cis-retinal generation is inhibited or abolished. Work by others has shown that patients with LCA2 have symptoms consistent with degenerating cones. In mouse models for LCA2, early cone degeneration is readily apparent: cone opsins and other proteins associated with the outer segment are delocalized and cell numbers decline rapidly within the first month. Rods would appear normal morphologically and functionally, if not for the absence of chromophore. Supplementation of mouse models of LCA2 with cis-retinoids has been shown to slow loss of cone photoreceptor cells if mice were maintained in darkness. Thus, 11-cis-retinal appears not only to have a role in the light response reaction but also to promote proper trafficking of the cone opsins and maintain viable cones.

Human infrared vision is triggered by two-photon chromophore isomerization.

Vision relies on photoactivation of visual pigments in rod and cone photoreceptor cells of the retina. The human eye structure and the absorption spectra of pigments limit our visual perception of light. Our visual perception is most responsive to stimulating light in the 400- to 720-nm (visible) range. First, we demonstrate by psychophysical experiments that humans can perceive infrared laser emission as visible light. Moreover, we show that mammalian photoreceptors can be directly activated by near infrared light with a sensitivity that paradoxically increases at wavelengths above 900 nm, and display quadratic dependence on laser power, indicating a nonlinear optical process. Biochemical experiments with rhodopsin, cone visual pigments, and a chromophore model compound 11-cis-retinyl-propylamine Schiff base demonstrate the direct isomerization of visual chromophore by a two-photon chromophore isomerization. Indeed, quantum mechanics modeling indicates the feasibility of this mechanism. Together, these findings clearly show that human visual perception of near infrared light occurs by two-photon isomerization of visual pigments.

Lake and sea populations of Mysis relicta (Crustacea, Mysida) with different visual-pigment absorbance spectra use the same A1 chromophore.

Glacial-relict species of the genus Mysis (opossum shrimps) inhabiting both fresh-water lakes and brackish sea waters in northern Europe show a consistent lake/sea dichotomy in eye spectral sensitivity. The absorbance peak (λmax) recorded by microspectrophotometry in isolated rhabdoms is invariably 20–30 nm red-shifted in “lake” compared with “sea” populations. The dichotomy holds across species, major opsin lineages and light environments. Chromophore exchange from A1 to A2 (retinal → 3,4-didehydroretinal) is a well-known mechanism for red-shifting visual pigments depending on environmental conditions or stages of life history, present not only in fishes and amphibians, but in some crustaceans as well. We tested the hypothesis that the lake/sea dichotomy in Mysis is due to the use of different chromophores, focussing on two populations of M. relicta from, respectively, a Finnish lake and the Baltic Sea. They are genetically very similar, having been separated for less than 10 kyr, and their rhabdoms show a typical lake/sea difference in λmax (554 nm vs. 529 nm). Gene sequencing has revealed no differences translating into amino acid substitutions in the transmembrane parts of their opsins. We determined the chromophore identity (A1 or A2) in the eyes of these two populations by HPLC, using as standards pure chromophores A1 and A2 as well as extracts from bovine (A1) and goldfish (A2) retinas. We found that the visual-pigment chromophore in both populations is A1 exclusively. Thus the spectral difference between these two populations of M. relicta is not due to the use of different chromophores. We argue that this conclusion is likely to hold for all populations of M. relicta as well as its European sibling species.

Mapping the Excited State Potential Energy Surface of a Retinal Chromophore Model with Multireference and Equation-of-Motion Coupled-Cluster Methods.

The photoisomerization of the retinal chromophore of visual pigments proceeds along a complex reaction coordinate on a multidimensional surface that comprises a hydrogen-out-of-plane (HOOP) coordinate, a bond length alternation (BLA) coordinate, a single bond torsion and, finally, the reactive double bond torsion. These degrees of freedom are coupled with changes in the electronic structure of the chromophore and, therefore, the computational investigation of the photochemistry of such systems requires the use of a methodology capable of describing electronic structure changes along all those coordinates. Here, we employ the penta-2,4-dieniminium (PSB3) cation as a minimal model of the retinal chromophore of visual pigments and compare its excited state isomerization paths at the CASSCF and CASPT2 levels of theory. These paths connect the cis isomer and the trans isomer of PSB3 with two structurally and energetically distinct conical intersections (CIs) that belong to the same intersection space. MRCISD+Q energy profiles along these paths provide benchmark values against which other ab initio methods are validated. Accordingly, we compare the energy profiles of MRPT2 methods (CASPT2, QD-NEVPT2, and XMCQDPT2) and EOM-SF-CC methods (EOM-SF-CCSD and EOM-SF-CCSD(dT)) to the MRCISD+Q reference profiles. We find that the paths produced with CASSCF and CASPT2 are topologically and energetically different, partially due to the existence of a "locally excited" region on the CASPT2 excited state near the Franck-Condon point that is absent in CASSCF and that involves a single bond, rather than double bond, torsion. We also find that MRPT2 methods as well as EOM-SF-CCSD(dT) are capable of quantitatively describing the processes involved in the photoisomerization of systems like PSB3.

Origin and Evolution of Retinoid Isomerization Machinery in Vertebrate Visual Cycle: Hint from Jawless Vertebrates

In order to maintain visual sensitivity at all light levels, the vertebrate eye possesses a mechanism to regenerate the visual pigment chromophore 11-cis retinal in the dark enzymatically, unlike in all other taxa, which rely on photoisomerization. This mechanism is termed the visual cycle and is localized to the retinal pigment epithelium (RPE), a support layer of the neural retina. Speculation has long revolved around whether more primitive chordates, such as tunicates and cephalochordates, anticipated this feature. The two key enzymes of the visual cycle are RPE65, the visual cycle all-trans retinyl ester isomerohydrolase, and lecithin:retinol acyltransferase (LRAT), which generates RPE65’s substrate. We hypothesized that the origin of the vertebrate visual cycle is directly connected to an ancestral carotenoid oxygenase acquiring a new retinyl ester isomerohydrolase function. Our phylogenetic analyses of the RPE65/BCMO and N1pC/P60 (LRAT) superfamilies show that neither RPE65 nor LRAT orthologs occur in tunicates (Ciona) or cephalochordates (Branchiostoma), but occur in Petromyzon marinus (Sea Lamprey), a jawless vertebrate. The closest homologs to RPE65 in Ciona and Branchiostoma lacked predicted functionally diverged residues found in all authentic RPE65s, but lamprey RPE65 contained all of them. We cloned RPE65 and LRATb cDNAs from lamprey RPE and demonstrated appropriate enzymatic activities. We show that Ciona ß-carotene monooxygenase a (BCMOa) (previously annotated as an RPE65) has carotenoid oxygenase cleavage activity but not RPE65 activity. We verified the presence of RPE65 in lamprey RPE by immunofluorescence microscopy, immunoblot and mass spectrometry. On the basis of these data we conclude that the crucial transition from the typical carotenoid double bond cleavage functionality (BCMO) to the isomerohydrolase functionality (RPE65), coupled with the origin of LRAT, occurred subsequent to divergence of the more primitive chordates (tunicates, etc.) in the last common ancestor of the jawless and jawed vertebrates.

Conical Intersection and Potential Energy Surface Features of a Model Retinal Chromophore: Comparison of EOM-CC and Multireference Methods.

This work investigates the performance of equation-of-motion coupled-cluster (EOM-CC) methods for describing the changes in the potential energy surfaces of the penta-2,4-dieniminium cation, a reduced model of the retinal chromophore of visual pigments, due to dynamical electron correlation effects. The ground-state wave function of this model includes charge-transfer and diradical configurations whose weights vary along different displacements and are rapidly changing at the conical intersection between the ground and the first excited states, making the shape of the potential energy surface sensitive to a balanced description of nondynamical and dynamical correlation. Recently, variational (MRCISD) and perturbative (MRPT2) approaches for including dynamical correlation in CASSCF-based calculations were tested along three representative ground state paths. Here, we use the same three paths to compare the performance of single-reference EOM-CC methods against MRCISD and MRCISD+Q. We find that the spin-flip variant of EOM-CCSD with perturbative inclusion of triple excitations (dT or fT) produces potential energy profiles of the two lowest electronic states in quantitative agreement with MRCISD+Q (our highest-quality reference method). The nonparallelity errors and differences in vertical energy differences of the two surfaces along these scans are less than 1.4 kcal/mol (EOM-SF-CCSD(dT) versus MRCISD+Q). For comparison, the largest error of MRCISD versus MRCISD+Q is 1.7 kcal/mol. Our results show that the EOM-CC methods provide an alternative to multireference approaches and may be used to study photochemical systems like the one used in this work.

Dynamic Electron Correlation Effects on the Ground State Potential Energy Surface of a Retinal Chromophore Model.

The ground state potential energy surface of the retinal chromophore of visual pigments (e.g., bovine rhodopsin) features a low-lying conical intersection surrounded by regions with variable charge-transfer and diradical electronic structures. This implies that dynamic electron correlation may have a large effect on the shape of the force fields driving its reactivity. To investigate this effect, we focus on mapping the potential energy for three paths located along the ground state CASSCF potential energy surface of the penta-2,4-dieniminium cation taken as a minimal model of the retinal chromophore. The first path spans the bond length alternation coordinate and intercepts a conical intersection point. The other two are minimum energy paths along two distinct but kinetically competitive thermal isomerization coordinates. We show that the effect of introducing the missing dynamic electron correlation variationally (with MRCISD) and perturbatively (with the CASPT2, NEVPT2, and XMCQDPT2 methods) leads, invariably, to a stabilization of the regions with charge transfer character and to a significant reshaping of the reference CASSCF potential energy surface and suggesting a change in the dominating isomerization mechanism. The possible impact of such a correction on the photoisomerization of the retinal chromophore is discussed.