title: Ancient origins of RGK protein function: modulation of voltage-gated calcium channels preceded the protostome and deuterostome split.
abstract: RGK proteins, Gem, Rad, Rem1, and Rem2, are members of the Ras superfamily of small GTP-binding proteins that interact with Ca2+ channel β subunits to modify voltage-gated Ca2+ channel function. In addition, RGK proteins affect several cellular processes such as cytoskeletal rearrangement, neuronal dendritic complexity, and synapse formation. To probe the phylogenetic origins of RGK protein-Ca2+ channel interactions, we identified potential RGK-like protein homologs in genomes for genetically diverse organisms from both the deuterostome and protostome animal superphyla. RGK-like protein homologs cloned from Danio rerio (zebrafish) and Drosophila melanogaster (fruit flies) expressed in mammalian sympathetic neurons decreased Ca2+ current density as reported for expression of mammalian RGK proteins. Sequence alignments from evolutionarily diverse organisms spanning the protostome/deuterostome divide revealed conservation of residues within the RGK G-domain involved in RGK protein--Cavβ subunit interaction. In addition, the C-terminal eleven residues were highly conserved and constituted a signature sequence unique to RGK proteins but of unknown function. Taken together, these data suggest that RGK proteins, and the ability to modify Ca2+ channel function, arose from an ancestor predating the protostomes split from deuterostomes approximately 550 million years ago.
authors.affiliation: Laboratory of Molecular Physiology, Section on Transmitter Signaling, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, Maryland, United States of America.
authors.forename: Henry L
authors.initials: HL
authors.lastname: Puhl
authors.affiliation: Laboratory of Molecular Physiology, Section on Transmitter Signaling, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, Maryland, United States of America.
authors.forename: Van B
authors.initials: VB
authors.lastname: Lu
authors.affiliation: Laboratory of Molecular Physiology, Section on Transmitter Signaling, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, Maryland, United States of America.
authors.forename: Yu-Jin
authors.initials: YJ
authors.lastname: Won
authors.affiliation: Department of Biochemistry & Molecular Biology, Faculty of Life Sciences, Institute for Structural Biology, Tel Aviv University, Ramat Aviv, Israel.
authors.forename: Yehezkel
authors.initials: Y
authors.lastname: Sasson
authors.affiliation: Department of Biochemistry & Molecular Biology, Faculty of Life Sciences, Institute for Structural Biology, Tel Aviv University, Ramat Aviv, Israel.
authors.forename: Joel A
authors.initials: JA
authors.lastname: Hirsch
authors.affiliation: Laboratory of Molecular Physiology, Section on Model Synaptic Systems, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, Maryland, United States of America.
authors.forename: Fumihito
authors.initials: F
authors.lastname: Ono
authors.affiliation: Laboratory of Molecular Physiology, Section on Transmitter Signaling, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, Maryland, United States of America.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Ikeda
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D020746:Calcium Channels, L-Type / Q000235:genetics* / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster; D019143:Evolution, Molecular; D008969:Molecular Sequence Data; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015027:Zebrafish / Q000235:genetics* / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D020746:Calcium Channels, L-Type; D029721:Drosophila Proteins; C570832:Rem1 protein, rat; C490031:Rrad protein, rat; D029961:Zebrafish Proteins; C581695:Gem protein, rat; D020559:Monomeric GTP-Binding Proteins; C528471:REM2 protein, human; D018631:ras Proteins