title: Kalrn plays key roles within and outside of the nervous system.
abstract: BACKGROUND
  The human KALRN gene, which encodes a complex, multifunctional Rho GDP/GTP exchange factor, has been linked to cardiovascular disease, psychiatric disorders and neurodegeneration. Examination of existing Kalrn knockout mouse models has focused only on neuronal phenotypes. However, Kalirin was first identified through its interaction with an enzyme involved in the synthesis and secretion of multiple bioactive peptides, and studies in C.elegans revealed roles for its orthologue in neurosecretion.
  
  
  RESULTS
  We used a broad array of tests to evaluate the effects of ablating a single exon in the spectrin repeat region of Kalrn (KalSR(KO/KO)); transcripts encoding Kalrn isoforms containing only the second GEF domain can still be produced from the single remaining functional Kalrn promoter. As expected, KalSR(KO/KO) mice showed a decrease in anxiety-like behavior and a passive avoidance deficit. No changes were observed in prepulse inhibition of acoustic startle or tests of depression-like behavior. Growth rate, parturition and pituitary secretion of growth hormone and prolactin were deficient in the KalSR(KO/KO) mice. Based on the fact that a subset of Kalrn isoforms is expressed in mouse skeletal muscle and the observation that muscle function in C.elegans requires its Kalrn orthologue, KalSR(KO/KO) mice were evaluated in the rotarod and wire hang tests. KalSR(KO/KO) mice showed a profound decrease in neuromuscular function, with deficits apparent in KalSR(+/KO) mice; these deficits were not as marked when loss of Kalrn expression was restricted to the nervous system. Pre- and postsynaptic deficits in the neuromuscular junction were observed, along with alterations in sarcomere length.
  
  
  CONCLUSIONS
  Many of the widespread and diverse deficits observed both within and outside of the nervous system when expression of Kalrn is eliminated may reflect its role in secretory granule function and its expression outside of the nervous system.
authors.affiliation: Department of Neuroscience, University of Connecticut Health Science Center, Farmington, CT 06030-3401, USA.
authors.forename: Prashant
authors.initials: P
authors.lastname: Mandela
authors.forename: Maya
authors.initials: M
authors.lastname: Yankova
authors.forename: Lisa H
authors.initials: LH
authors.lastname: Conti
authors.forename: Xin-Ming
authors.initials: XM
authors.lastname: Ma
authors.forename: James
authors.initials: J
authors.lastname: Grady
authors.forename: Betty A
authors.initials: BA
authors.lastname: Eipper
authors.forename: Richard E
authors.initials: RE
authors.lastname: Mains
mesh_terms: D000818:Animals; D001007:Anxiety / Q000235:genetics; D001362:Avoidance Learning / Q000502:physiology; D001522:Behavior, Animal / Q000502:physiology*; D002490:Central Nervous System / Q000502:physiology* / Q000503:physiopathology*; D003863:Depression / Q000235:genetics; D005260:Female; D006128:Growth / Q000502:physiology; D013006:Growth Hormone / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D007266:Inhibition, Psychological; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009468:Neuromuscular Diseases / Q000235:genetics; D009469:Neuromuscular Junction / Q000235:genetics / Q000502:physiology* / Q000648:ultrastructure; D036801:Parturition / Q000235:genetics; D010902:Pituitary Gland; D061251:Primary Cell Culture; D011388:Prolactin / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D012518:Sarcomeres / Q000235:genetics; D055139:Sensory Gating / Q000502:physiology
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C548820:KALRN protein, mouse; D020033:Protein Isoforms; D011388:Prolactin; D013006:Growth Hormone