title: Dependence on a retinophilin/myosin complex for stability of PKC and INAD and termination of phototransduction.
abstract: Normal termination of signaling is essential to reset signaling cascades, especially those such as phototransduction that are turned on and off with great rapidity. Genetic approaches in Drosophila led to the identification of several proteins required for termination, including protein kinase C (PKC), NINAC (neither inactivation nor afterpotential C) p174, which consists of fused protein kinase and myosin domains, and a PDZ (postsynaptic density-95/Discs Large/zona occludens-1) scaffold protein, INAD (inactivation no afterpotential D). Here, we describe a mutation affecting a poorly characterized but evolutionarily conserved protein, Retinophilin (Retin), which is expressed primarily in the phototransducing compartment of photoreceptor cells, the rhabdomeres. Retin and NINAC formed a complex and were mutually dependent on each other for expression. Loss of retin resulted in an age-dependent impairment in termination of phototransduction. Mutations that affect termination of the photoresponse typically lead to a reduction in levels of the major rhodopsin (Rh1) to attenuate signaling. Consistent with the slower termination in retin(1), the mutant photoreceptor cells exhibited increased endocytosis of Rh1 and a decline in Rh1 protein. The slower termination in retin(1) was a consequence of a cascade of defects, which began with the reduction in NINAC p174 levels. The diminished p174 concentration caused a decrease in INAD. Because PKC requires interaction with INAD for protein stability, this leads to reduction in PKC levels. The decline in PKC was age dependent and paralleled the onset of the termination phenotype in retin(1) mutant flies. We conclude that the slower termination of the photoresponse in retin(1) resulted from a requirement for the Retin/NINAC complex for stability of INAD and PKC.
authors.affiliation: Department of Biological Chemistry and Neuroscience, Center for Sensory Biology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Kartik
authors.initials: K
authors.lastname: Venkatachalam
authors.forename: David
authors.initials: D
authors.lastname: Wasserman
authors.forename: Xiaoyue
authors.initials: X
authors.lastname: Wang
authors.forename: Ruoxia
authors.initials: R
authors.lastname: Li
authors.forename: Eric
authors.initials: E
authors.lastname: Mills
authors.forename: Rebecca
authors.initials: R
authors.lastname: Elsaesser
authors.forename: Hong-Sheng
authors.initials: HS
authors.lastname: Li
authors.forename: Craig
authors.initials: C
authors.lastname: Montell
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D004330:Drosophila; D029721:Drosophila Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D004795:Enzyme Stability / Q000502:physiology; D005136:Eye Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D055537:Light Signal Transduction / Q000502:physiology*; D018995:Myosin Heavy Chains / Q000737:chemistry / Q000502:physiology*; D009218:Myosins / Q000737:chemistry / Q000502:physiology*; D010775:Photic Stimulation / Q000379:methods; D011493:Protein Kinase C / Q000737:chemistry / Q000502:physiology*
chemical_list: D029721:Drosophila Proteins; D005136:Eye Proteins; C091568:inaD protein, Drosophila; C520357:rtp protein, Drosophila; D011493:Protein Kinase C; C072308:ninaC protein, Drosophila; D018995:Myosin Heavy Chains; D009218:Myosins