A Role for Kalirin in the Response of Rat Medium Spiny Neurons to Cocaine

Ma, Xin−Ming; Huang, Jianping; Xin, Xiaonan; Yan, Yan; Mains, Richard E.; Eipper, Betty A.

doi:10.1124/mol.112.080044

Cited by 12 publications

(7 citation statements)

References 61 publications

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“…The ability of repeated cocaine exposure to increase spine density in NAc neurons requires the presence of Kal7 15 . Consistent with this, spine formation in cultures of rat medium spiny neurons is increased in response to expression of exogenous Kal7 82 . Perhaps more strikingly, Kal7 KO mice self-administer cocaine at a much higher rate than WT mice, and exhibit significantly elevated locomotor responses to injected cocaine 13, 15 .…”

Section: Resultssupporting

confidence: 72%

Brain Region and Isoform-Specific Phosphorylation Alters Kalirin SH2 Domain Interaction Sites and Calpain Sensitivity

Miller¹,

Yan²,

Machida³

et al. 2017

ACS Chem. Neurosci.

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Kalirin7 (Kal7), a postsynaptic Rho GDP/GTP exchange factor (RhoGEF), plays a crucial role in long term potentiation and in the effects of cocaine on behavior and spine morphology. The KALRN gene has been linked to schizophrenia and other disorders of synaptic function. Mass spectrometry was used to quantify phosphorylation at 26 sites in Kal7 from individual adult rat nucleus accumbens and prefrontal cortex before and after exposure to acute or chronic cocaine. Region- and isoform-specific phosphorylation was observed along with region-specific effects of cocaine on Kal7 phosphorylation. Evaluation of the functional significance of multi-site phosphorylation in a complex protein like Kalirin is difficult. With the identification of five tyrosine phosphorylation (pY) sites, a panel of 71 SH2 domains was screened, identifying subsets that interacted with multiple pY sites in Kal7. In addition to this type of reversible interaction, endoproteolytic cleavage by calpain plays an essential role in long-term potentiation. Calpain cleaved Kal7 at two sites, separating the N-terminal domain, which affects spine length, and the PDZ binding motif from the GEF domain. Mutations preventing phosphorylation did not affect calpain sensitivity or GEF activity; phosphomimetic mutations at specific sites altered protein stability, increased calpain sensitivity and reduced GEF activity.

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Section: Resultssupporting

confidence: 72%

Brain Region and Isoform-Specific Phosphorylation Alters Kalirin SH2 Domain Interaction Sites and Calpain Sensitivity

Miller¹,

Yan²,

Machida³

et al. 2017

ACS Chem. Neurosci.

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“…6A); statistics and actual levels of expression are provided in Table 1. Similar to prior analyses of Kal7 RNA and protein expression in rodents receiving experimenter administered cocaine (Kiraly et al, 2010b;Mains et al, 2011;Ma et al, 2012), analysis of Kal7 transcripts in Wt mice revealed an increase after cocaine self-administration, with no signal in Kal7 KO mice ( Fig. 6A; Table 1).…”

Section: Resultssupporting

confidence: 49%

“…Chronic cocaine exposure produces a wide variety of changes in gene expression, and Kalrn has been identified as a cocaineresponsive gene (Kiraly et al, 2010b;Mains et al, 2011;Ma et al, 2012). Kalrn is a large, alternatively spliced gene that yields multiple protein products (Kiraly et al, 2010a); Kal7 and DKal7 are absent in Kal7 KO mice, whereas expression of the larger isoforms, Kal9 and Kal12, is increased when the single exon unique to Kal7 and DKal7 is deleted (Ma et al, 2008b).…”

Section: Resultsmentioning

confidence: 99%

Constitutive Knockout of Kalirin-7 Leads to Increased Rates of Cocaine Self-Administration

et al. 2013

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Kalirin-7 (Kal7) is a Rho-guanine nucleotide exchange factor that is localized in neuronal postsynaptic densities. Kal7 interacts with the NR2B subunit of the NMDA receptor and regulates aspects of dendritic spine dynamics both in vitro and in vivo. Chronic treatment with cocaine increases dendritic spine density in the nucleus accumbens (NAc) of rodents and primates. Kal7 mRNA and protein are upregulated in the NAc following cocaine treatment, and the presence of Kal7 is necessary for the normal proliferation of dendritic spines following cocaine use. Mice that constitutively lack Kal7 [Kalirin-7 knockout mice (Kal7 KO )] demonstrate increased locomotor sensitization to cocaine and a decreased place preference for cocaine. Here, using an intravenous cocaine self-administration paradigm, Kal7 KO mice exhibit increased administration of cocaine at lower doses as compared with wildtype (Wt) mice. Analyses of mRNA transcript levels from the NAc of mice that self-administered saline or cocaine reveal that larger splice variants of the Kalrn gene are increased by cocaine more dramatically in Kal7 KO mice than in Wt mice. Additionally, transcripts encoding the NR2B subunit of the NMDA receptor increased in Wt mice that self-administered cocaine but were unchanged in similarly experienced Kal7 KO mice. These findings suggest that Kal7 participates in the reinforcing effects of cocaine, and that Kal7 and cocaine interact to alter the expression of genes related to critical glutamatergic signaling pathways in the NAc.

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“…It was found that the SynCAM1 is required to maintain the increased density of spines on NAc MSNs induced by chronic cocaine in rodent models of addiction (Giza et al, 2013). Kalirin 7, one of the Rho-guanosine diphosphate/guanosine triphosphate exchange factors (Rho-GEFs) known to play an important role in spine morphogenesis, has also recently been recognized as an essential determinant of dendritic spine formation following chronic cocaine exposure (Kiraly et al, 2010; Mains et al, 2011; Ma et al, 2012). Other factors recently shown to affect spine density in the NAc of rats and mice after chronic cocaine exposure include DNA methylation, increases in actin cycling and activation of the nuclear factor kappa B (NFkappaB) (Russo et al, 2009; LaPlant et al, 2010; Toda et al, 2010).…”

Section: Is Mef2 the Common Regulator Of Striatal Spine Changes Inmentioning

confidence: 99%

Differential striatal spine pathology in Parkinson’s disease and cocaine addiction: A key role of dopamine?

Villalba

Smith

2013

Neuroscience

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In the striatum, the dendritic tree of the two main populations of projection neurons, called “Medium Spiny Neurons (MSNs)”, are covered with spines that receive glutamatergic inputs from the cerebral cortex and thalamus. In Parkinson’s disease (PD), striatal MSNs undergo an important loss of dendritic spines, whereas aberrant overgrowth of striatal spines occurs following chronic cocaine exposure. This review examines the possibility that opposite dopamine dysregulation is one of the key factors that underlies these structural changes. In PD, nigrostriatal dopamine degeneration results in a significant loss of dendritic spines in the dorsal striatum, while rodents chronically exposed to cocaine and other psychostimulants, display an increase in the density of “thin and immature” spines in the nucleus accumbens (NAc). In rodent models of PD, there is evidence that D2 dopamine receptor-containing MSNs are preferentially affected, while D1-positive cells are the main targets of increased spine density in models of addiction. However, such specificity remains to be established in primates. Although the link between the extent of striatal spine changes and the behavioral deficits associated with these disorders remains controversial, there is unequivocal evidence that glutamatergic synaptic transmission is significantly altered in both diseased conditions. Recent studies have suggested that opposite calcium-mediated regulation of the transcription factor myocyte enhancer factor 2 (MEF2) function induces these structural defects. In conclusion, there is strong evidence that dopamine is a major, but not the sole, regulator of striatal spine pathology in PD and addiction to psychostimulants. Further studies of the role of glutamate and other genes associated with spine plasticity in mediating these effects are warranted.

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A Role for Kalirin in the Response of Rat Medium Spiny Neurons to Cocaine

Cited by 12 publications

References 61 publications

Brain Region and Isoform-Specific Phosphorylation Alters Kalirin SH2 Domain Interaction Sites and Calpain Sensitivity

Brain Region and Isoform-Specific Phosphorylation Alters Kalirin SH2 Domain Interaction Sites and Calpain Sensitivity

Constitutive Knockout of Kalirin-7 Leads to Increased Rates of Cocaine Self-Administration

Differential striatal spine pathology in Parkinson’s disease and cocaine addiction: A key role of dopamine?

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