Mechanism of extrasynaptic dopamine signaling in Caenorhabditis elegans

D1-like and D2-like dopamine receptors have synergistic and antagonistic effects on behavior. To understand the mechanisms underlying these effects, we studied dopamine signaling genetically in Caenorhabditis elegans. Knocking out a D2-like receptor, DOP-3, caused locomotion defects similar to those observed in animals lacking dopamine. Knocking out a D1-like receptor, DOP-1, reversed the defects of the DOP-3 knockout. DOP-3 and DOP-1 have their antagonistic effects on locomotion by acting in the same motor neurons, which coexpress the receptors and which are not postsynaptic to dopaminergic neurons. In a screen for mutants unable to respond to dopamine, we identified four genes that encode components of the antagonistic Gαo and Gαq signaling pathways, including Gαo itself and two subunits of the regulator of G protein signaling (RGS) complex that inhibits Gαq. Our results indicate that extrasynaptic dopamine regulates C. elegans locomotion through D1- and D2-like receptors that activate the antagonistic Gαq and Gαo signaling pathways, respectively.

[1]  D. Weinberger,et al.  Dopamine, the prefrontal cortex and schizophrenia , 1997, Journal of psychopharmacology.

[2]  David H. Hall,et al.  Neurotoxin-induced degeneration of dopamine neurons in Caenorhabditis elegans , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[3]  A. D. Smith,et al.  Immunocytochemical localization of D1 and D2 dopamine receptors in the basal ganglia of the rat: Light and electron microscopy , 1995, Neuroscience.

[4]  H. Horvitz,et al.  EGL-10 Regulates G Protein Signaling in the C. elegans Nervous System and Shares a Conserved Domain with Many Mammalian Proteins , 1996, Cell.

[5]  G. Patikoglou,et al.  Two RGS proteins that inhibit Gαo and Gαq signaling in C. elegans neurons require a Gβ5-like subunit for function , 2001, Current Biology.

[6]  S. R. Nash,et al.  Dopamine receptors: from structure to function. , 1998, Physiological reviews.

[7]  J. B. Justice,et al.  Dopamine D1/D2 agonists injected into nucleus accumbens and ventral pallidum differentially affect locomotor activity depending on site , 1999, Neuroscience.

[8]  P. Sternberg,et al.  Antagonism between Goα and Gqα in Caenorhabditis elegans: the RGS protein EAT-16 is necessary for Goα signaling and regulates Gqα activity , 1999 .

[9]  L. Ségalat,et al.  Modulation of serotonin-controlled behaviors by Go in Caenorhabditis elegans , 1995, Science.

[10]  J. Kaplan,et al.  Facilitation of Synaptic Transmission by EGL-30 Gqα and EGL-8 PLCβ DAG Binding to UNC-13 Is Required to Stimulate Acetylcholine Release , 1999, Neuron.

[11]  Wiklund Ra,et al.  First of two parts , 1997 .

[12]  Hilla Peretz,et al.  Ju n 20 03 Schrödinger ’ s Cat : The rules of engagement , 2003 .

[13]  K. Miller,et al.  Goα and Diacylglycerol Kinase Negatively Regulate the Gqα Pathway in C. elegans , 1999, Neuron.

[14]  D. van der Kooy,et al.  Dopamine modulates the plasticity of mechanosensory responses in Caenorhabditis elegans , 2004, The EMBO journal.

[15]  J. Waddington,et al.  Congenic D1A Dopamine Receptor Mutants: Ethologically Based Resolution of Behavioural Topography Indicates Genetic Background as a Determinant of Knockout Phenotype , 2003, Neuropsychopharmacology.

[16]  K. Jakobs,et al.  G protein specificity in receptor-effector coupling. Analysis of the roles of G0 and Gi2 in GH4C1 pituitary cells. , 1994, The Journal of biological chemistry.

[17]  L. Avery,et al.  The genetics of feeding in Caenorhabditis elegans. , 1993, Genetics.

[18]  F. Gonon.  Prolonged and Extrasynaptic Excitatory Action of Dopamine Mediated by D1 Receptors in the Rat Striatum In Vivo , 1997, The Journal of Neuroscience.

[19]  P. Sternberg,et al.  Homologous and unique G protein alpha subunits in the nematode Caenorhabditis elegans. , 1991, Cell regulation.

[20]  H. V. Van Tol,et al.  Dopamine signaling in Caenorhabditis elegans-potential for parkinsonism research. , 2001, Parkinsonism & related disorders.

[21]  E. Cuppen,et al.  The G-protein beta-subunit GPB-2 in Caenorhabditis elegans regulates the G(o)alpha-G(q)alpha signaling network through interactions with the regulator of G-protein signaling proteins EGL-10 and EAT-16. , 2001, Genetics.

[22]  J. Girault,et al.  Gαolf is necessary for coupling D1 and A2a receptors to adenylyl cyclase in the striatum , 2001, Journal of neurochemistry.

[23]  M. Low,et al.  Locomotor Activity in D2 Dopamine Receptor-Deficient Mice Is Determined by Gene Dosage, Genetic Background, and Developmental Adaptations , 1998, The Journal of Neuroscience.

[24]  S. Ishiura,et al.  Identification of a dopamine receptor from Caenorhabditis elegans , 2002, Neuroscience Letters.

[25]  B. Bloch,et al.  Ultrastructural localization of D1 dopamine receptor immunoreactivity in rat striatonigral neurons and its relation with dopaminergic innervation , 1996, Brain Research.

[26]  S. Senogles.  The D2 dopamine receptor isoforms signal through distinct Gi alpha proteins to inhibit adenylyl cyclase. A study with site-directed mutant Gi alpha proteins. , 1994, The Journal of biological chemistry.

[27]  L. Avery,et al.  LIM homeobox gene-dependent expression of biogenic amine receptors in restricted regions of the C. elegans nervous system. , 2003, Developmental biology.

[28]  A. Lang,et al.  Parkinson's disease. First of two parts. , 1998, The New England journal of medicine.

[29]  J. Lewis,et al.  Levamisole-resitant mutants of the nematode Caenorhabditis elegans appear to lack pharmacological acetylcholine receptors , 1980, Neuroscience.

[30]  Hans Forssberg,et al.  Anatomical and physiological evidence for D1 and D2 dopamine receptor colocalization in neostriatal neurons , 2000, Nature Neuroscience.

[31]  S. W. Emmons,et al.  Patterning of dopaminergic neurotransmitter identity among Caenorhabditis elegans ray sensory neurons by a TGFbeta family signaling pathway and a Hox gene. , 1999, Development.

[32]  W. Schafer,et al.  A calcium-channel homologue required for adaptation to dopamine and serotonin in Caenorhabditis elegans , 1995, Nature.

[33]  E. Cuppen,et al.  The G-Protein b-Subunit GPB-2 in Caenorhabditis elegans Regulates the Goa–Gqa Signaling Network Through Interactions With the Regulator of G-Protein Signaling Proteins EGL-10 and EAT-16 , 2001 .

[34]  J. Thomas,et al.  Calcium/calmodulin-dependent protein kinase II regulates Caenorhabditis elegans locomotion in concert with a G(o)/G(q) signaling network. , 2000, Genetics.

[35]  H. Horvitz,et al.  Coordinated Transcriptional Regulation of the unc-25Glutamic Acid Decarboxylase and the unc-47 GABA Vesicular Transporter by the Caenorhabditis elegans UNC-30 Homeodomain Protein , 1999, The Journal of Neuroscience.

[36]  R. Blakely,et al.  The Caenorhabditis elegans dopaminergic system: opportunities for insights into dopamine transport and neurodegeneration. , 2003, Annual review of pharmacology and toxicology.

[37]  W. Kostowski,et al.  Interaction between accumbens D1 and D2 receptors regulating rat locomotor activity , 2004, Psychopharmacology.

[38]  A. Takahashi,et al.  Regulation of Dopamine D1 and D2 Receptors on Striatal Acetylcholine Release in Rats , 1997, Brain Research Bulletin.

[39]  L. Birnbaumer,et al.  Most central nervous system D2 dopamine receptors are coupled to their effectors by Go , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[40]  James H. Thomas,et al.  Calcium / Calmodulin-Dependent Protein Kinase II Regulates Caenorhabditis elegans Locomotion in Concert With a Go / Gq Signaling Network , 2000 .

[41]  Leon Avery,et al.  eat-11 encodes GPB-2, a Gβ5 ortholog that interacts with Goα and Gqα to regulate C. elegans behavior , 2001, Current Biology.

[42]  F. Bloom,et al.  Neuroscience of Addiction , 1998, Neuron.

[43]  L. Avery,et al.  Mutations in a C. elegans Gqα Gene Disrupt Movement, Egg Laying, and Viability , 1996, Neuron.

[44]  H Y Wang,et al.  Evidence for the coupling of Gq protein to D1-like dopamine sites in rat striatum: possible role in dopamine-mediated inositol phosphate formation. , 1995, Molecular pharmacology.

[45]  T. Kimura,et al.  Differential Expression of an Acidic Domain in the Amino-terminal Propeptide of Mouse Pro-2(XI) Collagen by Complex Alternative Splicing (*) , 1995, The Journal of Biological Chemistry.

[46]  S. Hallam,et al.  The C. elegans NeuroD homolog cnd-1 functions in multiple aspects of motor neuron fate specification. , 2000, Development.

[47]  S. Brenner,et al.  The structure of the nervous system of the nematode Caenorhabditis elegans. , 1986, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[48]  Jeremy Mendel,et al.  Participation of the protein Go in multiple aspects of behavior in C. elegans , 1995, Science.

[49]  A. V. Maricq,et al.  Neuronal Control of Locomotion in C. elegans Is Modified by a Dominant Mutation in the GLR-1 Ionotropic Glutamate Receptor , 1999, Neuron.

[50]  J. Girault,et al.  In vivo release of [3H]γ-aminobutyric acid in the rat neostriatum—II. Opposing effects of D1 and D2 dopamine receptor stimulation in the dorsal caudate putamen , 1986, Neuroscience.

[51]  S. Ishiura,et al.  Cloning and characterization of a Caenorhabditis elegans D2‐like dopamine receptor , 2003, Journal of neurochemistry.

[52]  Rajesh Ranganathan,et al.  C. elegans Locomotory Rate Is Modulated by the Environment through a Dopaminergic Pathway and by Experience through a Serotonergic Pathway , 2000, Neuron.

[53]  A. Sidhu,et al.  Coupling of Human D-1 Dopamine Receptors to Different Guanine Nucleotide Binding Proteins. EVIDENCE THAT D-1 DOPAMINE RECEPTORS CAN COUPLE TO BOTH Gs AND Go(*) , 1995, The Journal of Biological Chemistry.

[54]  J. Kaplan,et al.  Serotonin Inhibition of Synaptic Transmission Gαo Decreases the Abundance of UNC-13 at Release Sites , 1999, Neuron.

[55]  R. Tsien,et al.  A monomeric red fluorescent protein , 2002, Proceedings of the National Academy of Sciences of the United States of America.