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Last update 08 May 2025

KALRN

Last update 08 May 2025

Basic Info

Synonyms

ARHGEF24, DUET, DUO

+ [11]

Introduction

Promotes the exchange of GDP by GTP. Activates specific Rho GTPase family members, thereby inducing various signaling mechanisms that regulate neuronal shape, growth, and plasticity, through their effects on the actin cytoskeleton. Induces lamellipodia independent of its GEF activity.

Drugs associated with KALRN

US20250101004

Patent Mining

Target

KALRN

Mechanism

KALRN inhibitors

Active Org.

Northwestern University

Originator Org.

Northwestern University

Active Indication

Arthritis Pain [+1]

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with KALRN

100 Translational Medicine associated with KALRN

0 Patents (Medical) associated with KALRN

225

Literatures (Medical) associated with KALRN

01 Mar 2025·YAKUGAKU ZASSHI

Neonatal Malnutrition Impacts Fibroblast Growth Factor 21-induced Neurite Outgrowth and Growth Hormone-releasing Hormone Secretion in Neonatal Mouse Brain

Review

Author: Hanaki, Ken-Ichi ; Shinomiya, Ai ; Oikawa, Mana ; Watanabe, Yoshifumi ; Yoshida, Yuko ; Shimada, Taiga

Neonatal malnutrition has been suggested as a factor contributing to neurological and other disorders. However, the details of this mechanism remain unclear. We focused on fibroblast growth factor 21 (FGF21), an endocrine factor produced in the liver during lactation-the main source of nutrition during the neonatal period- and analyzed its role in the brain. From the RNA-seq analysis of mouse brains, we analyzed the genes whose expression was regulated by FGF21 and their respective functions. We found that FGF21 has two functions in the neonatal brain; FGF21 induces the production of growth hormone-releasing hormone (GHRH) in the hypothalamus and is involved in isoform determination of Kalirin, a Ras homologous guanine nucleotide exchange factor, and promotes neurite outgrowth in the brain. Furthermore, the above mechanism is regulated by SH2-containing tyrosine phosphatase (SHP2) activity downstream of the FGF receptor. Additionally, the conserved intron of the SHP2 gene, Ptpn11, shows altered activity in malnourished mouse brains. In summary, FGF21 functions in neurite outgrowth and GHRH production in the neonatal mouse brain, with the mechanism being regulated by SHP2. However, SHP2 activity depends on nutritional status. Our goal was to elucidate the mechanisms by which FGF21 is involved in the maintenance of the central nervous system during the neonatal period. This study provides new insights into the role of FGF21 in diseases caused by dysfunction due to malnutrition.

03 Dec 2024·Cerebral Cortex

Identification and characterization of human KALRN mRNA and Kalirin protein isoforms

Article

Author: Hengerer, Bastian ; Bornemann, Klaus D ; Mould, Arne W ; Brennan, Paul E ; von Delft, Annette ; Tunbridge, Elizabeth M ; Haerty, Wilfried ; Hall, Nicola A L ; Drydale, Edward ; Wright, David J ; Harrison, Paul J ; Bancroft, James ; Pinnock, Rob

AbstractKalirin is a multidomain protein with important roles in neurite outgrowth, and synaptic spine formation and remodeling. Genetic and pathophysiological links with various neuropsychiatric disorders associated with synaptic dysfunction and cognitive impairment have sparked interest in its potential as a pharmacological target. Multiple Kalirin proteoforms are detected in the adult human brain, yet we know little about the diversity of the transcripts that encode them or their tissue profiles. Here, we characterized full-length KALRN transcripts expressed in the adult human frontal lobe and hippocampus using rapid amplification of complementary DNA (cDNA) ends and nanopore long-read sequencing. For comparison with non-neural tissue, we also analyzed KALRN transcripts in the aorta. Multiple novel isoforms were identified and were largely similar between the two brain regions analyzed. Alternative splicing in the brain results in preferential inclusion of exon 37, which encodes 32 amino acids upstream of the second guanine nucleotide exchange factor (GEF) domain. Structural modeling predicts that a subset of these amino acids forms a conserved alpha helix. Although deletion of these amino acids had little effect on GEF activity, it did alter Kalirin-induced neurite outgrowth suggesting that this brain-enriched splicing event may be important for neural function. These data indicate that alternative splicing is potentially important for regulating Kalirin actions in the human brain.

01 Oct 2024·Brain Research Bulletin

GDNF facilitates cognitive function recovery following neonatal surgical-induced learning and memory impairment via activation of the RET pathway and modulation of downstream effectors PKMζ and Kalirin in rats

Article

Author: Li, Yi-Ze ; Yuan, Yuan ; Chen, Yi ; Jia, Zhen ; Zheng, Yu-Xin

OBJECTIVEThe aim of this study is to elucidate the underlying mechanism through which glial cell line-derived neurotrophic factor (GDNF) improves cognitive deficits in adults resulting from neonatal surgical interventions.METHODSNewborn Sprague-Dawley rats, regardless of gender, were randomly allocated into seven groups on postnatal day 7 as follows (n=15): (1) Control group (not subjected to anesthesia, surgery, or any pharmaceutical interventions); (2) GDNF group (received intracerebroventricular injection of GDNF); (3) Surgery group (underwent right carotid artery exposure under anesthesia with 3 % sevoflurane); (4) Surgery plus GDNF group; (5) Surgery plus GDNF and type II JAK inhibitor NVP-BBT594 (BBT594) group (administered intraperitoneal injection of BBT594); (6) BBT group; and (7) Surgery plus BBT group. Starting from postnatal day 33, all rats underwent Barnes maze and fear conditioning tests, followed by decapitation under sevoflurane anesthesia for subsequent analyses. The left hemibrains underwent Golgi staining, while the right hemibrains were used for hippocampal protein extraction to assess Protein kinase Mζ (PKMζ) and Kalirin expression through western blotting.RESULTSGDNF demonstrated a mitigating effect on spatial learning and memory impairment, as well as context-related fear memory impairment, reductions in dendritic total lengths, and spinal density within the hippocampus induced by surgical intervention. Notably, all of these ameliorative effects of GDNF were reversed upon administration of the RET inhibitor BBT594. Additionally, GDNF alleviated the downregulation of protein expression of PKMζ and Kalirin in the hippocampus of rats subjected to surgery, subsequently reversed by BBT594.CONCLUSIONThe effective impact of GDNF on learning and memory impairment caused by surgical intervention appears to be mediated through the RET pathway. Moreover, GDNF may exert its influence by upregulating the expression of PKMζ and Kalirin, consequently enhancing the development of dendrites and dendritic spines.

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KALRN

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