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Open Access Highly Accessed Research article

Kalrn plays key roles within and outside of the nervous system

Prashant Mandela1, Maya Yankova2, Lisa H Conti3, Xin-Ming Ma1, James Grady4, Betty A Eipper12 and Richard E Mains1*

Author affiliations

1 Department of Neuroscience, University of Connecticut Health Science Center, Farmington, CT, 06030-3401, USA

2 Molecular Microbial & Structural Biology, University of Connecticut Health Science Center, Farmington, CT, 06030-3401, USA

3 Psychiatry, University of Connecticut Health Science Center, Farmington, CT, 06030-3401, USA

4 Connecticut Institute Clinical Translational Science, University of Connecticut Health Science Center, Farmington, CT, 06030-3401, USA

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Citation and License

BMC Neuroscience 2012, 13:136  doi:10.1186/1471-2202-13-136

Published: 1 November 2012

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 (KalSRKO/KO); transcripts encoding Kalrn isoforms containing only the second GEF domain can still be produced from the single remaining functional Kalrn promoter. As expected, KalSRKO/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 KalSRKO/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, KalSRKO/KO mice were evaluated in the rotarod and wire hang tests. KalSRKO/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.

Keywords:
Neuromuscular junction; Rotarod; Grip strength; Anxiety; Passive avoidance; Rho-GEF