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Chapter 3

Vertebrate rhodopsin

Oliver P. Ernst, Klaus Peter Hofmann and Krzysztof Palczewski

Table of contents

Abstract 79

3.1 Introduction 79

3.2 Phototransduction 80

3.2.1 The disk membrane 80

3.2.2 G-protein and the effector activation 82

3.2.3 Deactivation 83

3.3 Structure of bovine rhodopsin 83

3.3.1 Overall topology 84

3.3.2 The inactive ground state 88

3.4 Photoisomerization of rhodopsin 90

3.4.1 Classical photoisomerization pathway 90

3.4.2 Early events - storage of photon energy in bathorhodopsin 91

3.4.3 Relaxation and steric trigger - lumirhodopsin and metarhodopsin I 92

3.5 Metarhodopsin II: the active photoproduct of rhodopsin 93

3.5.1 Metarhodopsin II 93

3.5.2 Role of the hydrophobic environment and light-induced reorganization of disk membrane phospholipids 95

3.5.3 Formation of the signaling state 96

3.5.4 Mechanistic insights from archaeal rhodopsins and photoreversal of metarhodopsin II 97

3.6 Interaction between photoactivated rhodopsin and G-protein . . 99

3.6.1 Stabilization of metarhodopsin II by Gt 99

3.6.2 The rhodopsin-Gt interface 99

3.6.2.1 Binding sites at Gt 100

3.6.2.2 Binding sites at rhodopsin 100

3.6.3 Conclusions 101

3.7 Interactions between photoactivated rhodopsin and arrestin and rhodopsin kinase 102

3.7.1 Arrestin 102

3.7.1.1 Arrestin-receptor interaction sites 102

3.7.1.2 Conformational switch 103

3.7.1.3 Molecular recognition 104

3.7.2 Rhodopsin kinase 104

3.7.2.1 Signaling state 104

3.7.2.2 Interaction sites 105

3.7.2.3 Direct competition 105

3.8 Light-independent signaling of different forms of the apoprotein 106

3.8.2 Retinal-opsin complexes 106

3.9 Metabolism of retinal 107

Acknowledgements 109

References 109

Abstract

Rhodopsin, described more than 120 years ago as the visual pigment of the retina, is a transmembrane protein composed of the apoprotein opsin and the covalently linked chromophore 11-m-retinal. It is highly expressed in rod cells, where it localizes to plasma and internal membranes of the rod outer segment, a specific cellular compartment dedicated for transformation of light energy into biochemical reactions. Absorption of light by the chromophore triggers transient conformational changes of the apoprotein, which in turn initiates the G-protein mediated enzymatic cascade of reactions, termed photo-transduction, that result in neuronal signaling. Rhodopsin is also the best-studied member of a large group of cell-surface receptors that signal through G-proteins and therefore are called G-protein-coupled receptors (GPCRs). Unique members of the GPCR superfamily are involved in a vast variety of specific cellular signal transduction processes including visual, taste and odor perceptions and sensing a variety of hormones. These receptors share a common seven-transmembrane a-helical structure and use the binding energy of extracellular chemical ligands for stabilization of an active receptor conformation. Thus, conformational changes of GPCRs allow transmission of the extracellular signal, across the plasma membrane, into the cell. Elucidation of the crystal structure of rhodopsin and characterization of fundamental aspects of the photoactivation mechanism paved the way for better understanding of other GPCRs. In this review, we describe the first steps in seeing, comprising light-induced activation of rhodopsin, and its interaction with proteins of the phototransduction cascade.

3.1 Introduction

In 1878, Kiihne and co-workers recognized that vision originates from the absorption of light by visual pigments [1,2]. These pigments are membrane-bound photoreceptor proteins composed of the apoprotein opsin and a retinal chromophore. In the retina of vertebrates, two main types of photoreceptor cells, rod and cone cells, are present. The rods are responsible for scotopic vision and several sub-types of cones for photopic vision. Rod visual pigment rhodopsin is a 40 kD integral membrane protein, which consists of the apoprotein opsin containing seven helices spanning the membrane and the prosthetic group 11-cw-retinal. The color of rhodopsin and its response to light arises from the covalent linkage of the 11-«¿-retinal chromophore. The chromophore is linked via a protonated Schiff base to Lys296 in helix VII, yielding a broad absorption with a maximum at 500 nm (e500 = 40,000 cm-1 M_1) that matches the solar spectrum. The human retina contains three sub-types of cone pigments that have distinct sensitivity to different wavelengths of visible light: blue, green and red pigments, with absorption maxima of 424, 530 and 560 nm, respectively [3], In principle, all visual pigments convert light energy into changes in the protein conformation, and in turn trigger intracellular reactions that ultimately lead to a neuronal impulse [4]. The prosthetic group that absorbs light (i.e. the chromophore) undergoes isomerization after photon absorption [5], and transmits the light energy to the chromophore-receptor complex, where it is initially stored as an energetically unfavorable conformation of the chromophore and an unstable tertiary conformation of the polypeptide chain. The signaling state of the receptor is then reached by a subsequent thermal relaxation process. The present chapter focusses on the most extensively studied visual pigment, rhodopsin.

Rod cells are capable of detecting single quanta [6], This ultimate sensitivity is achieved as a consequence of high probability of absorption of the incoming light, efficient photochemical reaction, a rapid, reproducible and greatly amplified intracellular signal transduction and a high signal-to-noise ratio of the overall transduction process. The visual system evolved just to perform such a task. A prerequisite of such signaling properties is for rhodopsin to have an extremely low dark activity. In the time domain of the electrical response, no spontaneous activation is tolerated from any of the 108 inactive rhodopsin molecules present in a photoreceptor cell. The estimated lifetime of the inactive state of rhodopsin is >10 years (see e.g. [4]). However, when rhodopsin is photoactivated, it initiates the transduction cascade with maximal quantum efficiency.

The phototransduction system is composed of the G-protein transducin (Gt), named according to its rod cell-specific expression of the a-subunit, and the effector, a cGMP-specific phoshodiesterase (reviewed in [7]). Therefore, rhodopsin is considered to be a member of a large group of transmembrane proteins of similar topology, termed G-protein-coupled receptors (GPCRs). Upon activation of GPCRs by ligand binding, or in the case of visual pigments by photon-induced alteration in the conformation of the bound ligand, the cytoplasmic surface of GPCRs becomes competent for G-protein binding, leading to subsequent catalytic GDP/GTP exchange on the a-subunit and G-protein activation. In general, GPCRs serve to respond to chemical signals and transmit them across biological membranes by coupling to heterotrimeric guanine nucleotide-binding proteins (G-proteins), which in turn, modulate effector protein activity and thereby affect second messenger levels (reviewed by [8]).

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