VAAvA

Rhodopsin (P) hv Metarhodopsin (M)

De phosphorylation 4*

Release of RDGC (rdgc j

Binding of Arrestin2

p p WEOp j Arr2

'nteraction /

Kith Rhodopsin t

┬░hosohatase I

Photo reg eneration of M to P

Release of Arrestin2 p p

Binding of Arrestin2

Photo reg eneration of M to P

Release of Arrestin2 p p

Interaction with

Rhodopsin Kinase

Phosphorylation of M

Interaction with

Rhodopsin Kinase

Phosphorylation of M

Endocytosis of the Metarhodopsin -Arrestin2 complex

Figure 5. Activation, inactivation and endocytosis of Drosophila rhodopsin. Absorption of a photon causes a conformational change in the rhodopsin molecule (P) and triggers the formation of the active metarhodopsin state (M). Red ellipses show rhodopsin (chromophore in the 11 -eis configuration), blue ellipses show metarhodopsin (chromophore in the al\-trans configuration). Active M triggers the phototransduction cascade by activation of the visual G-protein Gq. Binding of Arrestin2 (Arr2) inactivates M and is followed by phosphorylation of M through a yet unidentified rhodopsin kinase (RK). Arrestin-bound M is subject to Clathrin-mediated endocytosis. Upon photon capture, phosphorylated M is re-converted into phosphorylated P and releases bound Arr2. This enables phosphorylated P to be dephosphorylated through the action of the Retinal Degeneration C protein (= rhodopsin phosphatase), yielding the initial rhodopsin state.

Instead, phosphorylation of the M-state is part of a signalling mechanism that induces the endocytosis of M, an important step in the renewal pathway of rhodopsin. This pathway comprises of the integration of newly synthesized rhodopsin into the photoreceptor membrane and the endocytosis of meta-rhodopsin molecules. The renewal cycle guarantees a high level of rhodopsin in the photoreceptor membrane in a situation in which photoregeneration of rhodopsin cannot take place. The signalling capacity of the phosphorylated metarhodopsin-Arr2 complex (Figure 5) is not limited to metarhodopsin endocytosis. A defect in rhodopsin dephosphorylation, resulting from a null mutation in the rdgC gene which encodes the rhodopsin phosphatase, induces photoreceptor apoptosis [98], Apoptosis is also induced if the release of Arr2 from this complex is prevented [70]. The apparent switch in the function from an endocytosis control mechanism to a function in the control of the active rhodopsin state may have occurred in parallel with the development of a mechanism for the chemical regeneration of rhodopsin by vertebrates. Rhodopsin is here regenerated by the exchange of all -trans retinal for ll-c/s retinal. This step takes place at opsin molecules still located in the photoreceptor disc membrane. In vertebrates, a need for selective labelling of metarhodopsin for endocytosis no longer exists as photoreceptor disc membranes are shedded from the photoreceptor tips as a whole, and are then phagocytized by the pigment epithelium (reviewed in [99]).

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