title: Role for the membrane receptor guanylyl cyclase-C in attention deficiency and hyperactive behavior.
abstract: Midbrain dopamine neurons regulate many important behavioral processes, and their dysfunctions are associated with several human neuropsychiatric disorders such as attention deficit hyperactivity disorder (ADHD) and schizophrenia. Here, we report that these neurons in mice selectively express guanylyl cyclase-C (GC-C), a membrane receptor previously thought to be expressed mainly in the intestine. GC-C activation potentiates the excitatory responses mediated by glutamate and acetylcholine receptors via the activity of guanosine 3',5'-monophosphate-dependent protein kinase (PKG). Mice in which GC-C has been knocked out exhibit hyperactivity and attention deficits. Moreover, their behavioral phenotypes are reversed by ADHD therapeutics and a PKG activator. These results indicate important behavioral and physiological functions for the GC-C/PKG signaling pathway within the brain and suggest new therapeutic targets for neuropsychiatric disorders related to the malfunctions of midbrain dopamine neurons.
authors.affiliation: Graduate Program in Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Gong
authors.forename: Cheng
authors.initials: C
authors.lastname: Ding
authors.forename: Ji
authors.initials: J
authors.lastname: Hu
authors.forename: Yao
authors.initials: Y
authors.lastname: Lu
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Mann
authors.forename: Fuqiang
authors.initials: F
authors.lastname: Xu
authors.forename: Mitchell B
authors.initials: MB
authors.lastname: Cohen
authors.forename: Minmin
authors.initials: M
authors.lastname: Luo
mesh_terms: D000661:Amphetamine / Q000008:administration & dosage; D000818:Animals; D001288:Attention; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics / Q000378:metabolism*; D001522:Behavior, Animal / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004789:Enzyme Activation; D005768:Gastrointestinal Hormones / Q000378:metabolism / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D007175:Impulsive Behavior; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D045265:Natriuretic Peptides / Q000378:metabolism / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D000074261:Receptors, Enterotoxin; D017470:Receptors, Glutamate / Q000378:metabolism; D050705:Receptors, Guanylate Cyclase-Coupled / Q000235:genetics / Q000378:metabolism*; D011976:Receptors, Muscarinic / Q000378:metabolism; D018000:Receptors, Peptide / Q000235:genetics / Q000378:metabolism*; D012118:Resorcinols / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction; D013378:Substantia Nigra / Q000166:cytology / Q000378:metabolism*; D017557:Ventral Tegmental Area / Q000166:cytology / Q000378:metabolism*
chemical_list: D005768:Gastrointestinal Hormones; D008024:Ligands; D045265:Natriuretic Peptides; D017470:Receptors, Glutamate; D011976:Receptors, Muscarinic; D018000:Receptors, Peptide; D012118:Resorcinols; C072685:guanylin; C084362:uroguanylin; C079215:3,5-dihydroxyphenylglycine; D000661:Amphetamine; D017869:Cyclic GMP-Dependent Protein Kinases; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled; D006152:Cyclic GMP; D005998:Glycine; D004298:Dopamine