The deleterious impact of D153del mutation on GNB3 structure and its localization might suggest that it is very unlikely to form stable heterotrimers and heterodimers. Therefore the mutant GNB3dYFP is no longer considered as a bona fide resident in the ER and will probably be targeted for early degradation through the ubiquitin conjugated proteosomal pathway. In the normal visual transduction pathway, the Ga transducin subunit 2, is responsible for activating phosphodiesterases that hydrolyzes the synthesized cGMP from Guanate Cyclases. Therefore any decrease in PDE6b activation will result in an increase of cGMP due to less cleavage of these molecules. Moreover the lack of stable interaction with both the Gta2 transducin and Gc subunits will lead to the loss of photoactivation in cone cells. cGMP is a common regulator of ion channel conductance, glycogenolysis, and cellular apoptosis and also participates in synaptic signaling and neuronal cell physiology. Any alterations in cGMP levels may also change brain functional physiology. Insufficient cGMP levels observed in whole brain tissue suggests that cGMP-mediated pathways involving cGMP dependant gated ion channels, cGMP AbMole BI-9564 dependent kinases and cGMP controlled PDE��s as generators, effectors and modulators of neuronal development and function, are likely to be affected. The increase of cGMP has previously been shown to cause a continuous opening of cGMP dependant ion channels and lead to a drastically elevated Na + and Ca2+ flux. The extremely elevated ion levels may contribute primarily to disturbance in vision and secondarily, result in retinal dystrophies. As rge photoreceptors remain intact but become increasingly disorganized, it is possible that significant alterations in the expression of connexin proteins, which are observed in the PDE6b rd mouse, may also be occurring. Gtb2 is also known to inhibit ACs and due to its lower activation results in less or no transport to the membrane and inhibits ACs. Therefore high increases in cAMP levels generated in the rge eye suggests that they are likely to have fewer other activated alpha transducin subunits that bind to the unstable GNB3 subunit. High local levels of cAMP can be toxic to photoreceptor cells which become unresponsive to survival factors, due to altered signaling, and this may ultimately contribute to retinal dysfunction causing the cone cell disorganisation as observed in rge birds. Increased levels of cAMP can also activate protein kinases that are coupled to G proteins, especially GRK2. Increase in relative phosphorylation levels of GRK2 under basal conditions observed in rge retina is therefore due to an increase in the level of cAMP. This suggests that the likely mechanism altering the desensitization AbMole Crovatin kinetics of associated GPCR is due to the lack of both translocation and the binding of upregulated phospho GRK2 to the Gbc subunits at the plasma membrane.