Kalirin

Kalirin, also known as Huntingtin-associated protein-interacting protein (HAPIP), protein duo (DUO), or serine/threonine-protein kinase with Dbl- and pleckstrin homology domain, is a protein that in humans is encoded by the KALRN gene.[5][6] Kalirin was first identified in 1997 as a protein interacting with huntingtin-associated protein 1.[5] Is also known to play an important role in nerve growth and axonal development.[7]

KALRN
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesKALRN, ARHGEF24, CHD5, CHDS5, DUET, DUO, HAPIP, TRAD, kalirin, RhoGEF kinase, kalirin RhoGEF kinase
External IDsOMIM: 604605 MGI: 2685385 HomoloGene: 57160 GeneCards: KALRN
Gene location (Human)
Chr.Chromosome 3 (human)[1]
Band3q21.1-q21.2Start124,080,023 bp[1]
End124,726,325 bp[1]
Orthologs
SpeciesHumanMouse
Entrez

8997

545156

Ensembl

ENSG00000160145

ENSMUSG00000061751

UniProt

O60229

A2CG49

RefSeq (mRNA)

NM_001164268
NM_177357

RefSeq (protein)

NP_001157740
NP_796331

Location (UCSC)Chr 3: 124.08 – 124.73 MbChr 16: 33.97 – 34.57 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Kalirin is a member of the Dbl family of proteins and is a Rho guanine nucleotide exchange factor.

It is named after the multiple-handed Hindu goddess Kali for its ability to interact with numerous other proteins. Kalirin's other name, DUO, comes from the fact that it is 98% identical to rat DUO protein and 80.6% identical to a human protein named TRIO. Unlike TRIO, which is expressed in numerous tissues, Kalirin isoforms are mainly found in the brain.

Clinical significance

Several isoforms of Kalirin are produced through alternative splicing.[8] One of the isoforms, Kalirin-7, was found to be necessary for the remodeling of synapses in mature cortical neurons and is thought to be important in the development of schizophrenia,[9][10][11][12] as demonstrated by adolescent development of schizophrenia-like symptoms in kalirin knockout mice.[13] Alzheimer's disease may also be linked to kalirin-7.[12][14][15]

The KALRN gene, has been linked to multiple neurological disorders both through large exome and genome sequencing efforts, as well as post mortem and clinical studies.

Several mutations within KALRN have been linked to neurological disease. In autism spectrum disorder a frameshift mutation was found [16] that is likely to lead to transcript decay, and heterozygosity. Another, found within the second GEF domain, is predicted to be highly deleterious to RhoA-GEF activity and likely affects the function of kalirin9 and 12 isoforms early in neuronal development.[17] A patient harboring a homozygous mutation in kalirin’s spectrin repeat domain was found to have severe intellectual disability,[18] and both truncating and missense mutations have been identified in patients with developmental delay.[19] Several intronic variants have been associated with addiction and were found to alter the function of brain regions responsible for reward anticipation.[20] This link to addiction is supported by animal models, where loss of kalirin results in altered cocaine self-administration and synaptic and expression changes in response to cocaine.[21][22][23] Perhaps the most compelling genetic links are between kalirin and schizophrenia. Numerous missense mutations in KALRN have been identified in exome sequencing studies of schizophrenia cohorts [24] that are predicted to be deleterious to protein function.

Neuronal studies have provided insight into the mechanisms of some missense mutations, particularly within the GEF domains of KALRN. A mutation found within the Rac-GEF domain was found to induce strong reductions in Rac activation, neuronal branching and spine density.[25] These effects were mirrored by mutations in the RhoA-GEF domain, producing similar neuronal deficits, but by promoting RhoA-GEF activity.[26] In addition to exome sequencing, post-mortem studies have consistently found alterations in kalirin transcript levels within the brain [27][28] further supporting a role for kalirin in the etiology of schizophrenia.

In addition to neurodevelopmental disorders, kalirin has been found to be underexpressed in the post-mortem Alzheimer’s brain.[29][30] This loss of kalirin expression was recapitulated in animal models of Alzheimer’s disease.[31][32] Moreover, introduction of kalirin7 into culture [33] or animal models [32] of Alzheimer’s disease was able to rescue synaptic and behavioral deficits, suggesting an important role for kalirin in regulating synapse loss and cognitive impairment in Alzheimer’s disease.

Function

The majority of kalirin’s effects are induced through its catalytic GEF domain signaling. By promoting the release of GDP from Rac and RhoA , it acts as an activator of GTPase signaling within the cell.[34] Although able to activate Rac and RhoA, much of its activity in regulating neuronal morphology has been attributed to Rac-PAK pathway activation.[35] kalirin has found been found to exert control over dendritic arborization,[36] axonal growth,[34][37] dendritic spine formation [38] and synaptic activity [39][40] and plasticity.[39][41][42][43] These effects are regulated by protein-protein interactions and post-translational modifications within the non-catalytic domains, and have been shown to exert control over kalirin subcellular targeting and activation.[39][38][44]

Kalirin has been found to play a critical role in synaptic activity and plasticity. Loss of KALRN results in decreased nMDAr and AMPAr-mediated mEPSC,[40] and kalirin7 knockout animals show strong deficits in NMDAr mediated long term potentiation [40][42] and long term depression.[41] This may be linked to the ability to regulate RAC-PAK signaling and actin dynamics, which in turn can regulate the size and density of dendritic spines.[40] Within dendritic spines, kalirin interacts with multiple disease related proteins to regulate synapse strength. It directly interacts with the schizophrenia risk factor DISC1 that can act to suppress kalirin function within the spine.[45] Furthermore, kalirin7 directly interacts with the GluN2B subunit of the NMDA receptor [42] and PSD95 [46] within the post-synaptic density.

The importance of KALRN in neurodevelopment is supported by knockout animal models that display profound deficiencies in multiple behavioral tasks. Kalirin knockout animals display reduced GEF activity,[40] dendritic arborization and spine density.[47] These deficits may be linked to the observed reductions in prepulse inhibition, sociability and increased locomotor activity. Notably, loss of kalirin results in deficits in working memory, but not reference memory.[40][48] The generation of a kalirin7 specific knockout animal model revealed similar deficits in spine density,[48][49] suggesting a central role of kalirin7 in regulating neuronal connectivity. Both full and kalirin7 specific knockout animals show decreased anxiety-like behavior and impaired contextual fear learning.[49][50][51]

Expression

Multiple isoforms, arising from alternate splicing and promoter usage, display varying tissue and developmental expression.[52][53] Control over kalirin expression is exerted through the use of alternate promoters which produce alternate start sites and restrict expression to specific neuronal subpopulations, and alter kalirin activity within neurons.[54][55] During early development, the long kalirin9 and 12 isoforms are predominant in the brain. These isoforms contain both a Rac and a RhoA selective GEF domain, and control axonal growth and dendritic branching. Kalirin9 and 12 are also expressed ubiquitously throughout the body [56] and have functions outwith the brain. However, during neurodevelopment the kalirin7 isoform is preferentially expressed during periods of synaptogenesis, and this isoform displays highly restricted cortical expression.[56][57] Kalirin7 expresses only the N-terminal domains, including the Rac-GEF domain along with a c-terminal PDZ-binding domain that strongly targets kalirin7 to the post-synaptic density.[46] It is likely this subcellular distribution is vital to kalirin7 function, as this isoform exerts control dendritic spine density and synaptic plasticity. It is likely that mutations that result in deregulation of kalirin function within the brain is responsible for the role of kalirin within multiple neurological disorders.

References
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