CaMKII activation is a novel effector of alcohol’s neurotoxicity in neural crest stem/progenitor cells

Garic, Ana; Flentke, George R.; Amberger, Ed; Hernandez, M. Rosario; Smith, Susan

doi:10.1111/j.1471-4159.2011.07273.x

Cited by 48 publications

(62 citation statements)

References 68 publications

(138 reference statements)

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“…Although little is known about the role in alcohol addiction, alcohol affects CaMKII levels in the brain (Smith and Navratilova, 1999;McBride et al, 2009;Mahadev et al, 2001;Lee et al, 2011) and increases phosphorylation rate at Thr286 (Garic et al, 2011;Wang et al, 2012). Both may control alcohol effects on cellular signaling (Liu et al, 2006;Xu et al, 2008), behavior (Kim et al, 2012;Wang et al, 2012), and neurotoxicity (Garic et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

αCaMKII Autophosphorylation Controls the Establishment of Alcohol Drinking Behavior

Easton

Lucchesi

Lourdusamy

et al. 2013

Neuropsychopharmacol

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The a-Ca 2 þ /calmodulin-dependent protein kinase II (aCaMKII) is a crucial enzyme controlling plasticity in the brain. The autophosphorylation of aCaMKII works as a 'molecular memory' for a transient calcium activation, thereby accelerating learning. We investigated the role of aCaMKII autophosphorylation in the establishment of alcohol drinking as an addiction-related behavior in mice. We found that alcohol drinking was initially diminished in aCaMKII autophosphorylation-deficient aCaMKII T286A mice, but could be established at wild-type level after repeated withdrawals. The locomotor activating effects of a low-dose alcohol (2 g/kg) were absent in aCaMKII T286A mice, whereas the sedating effects of high-dose (3.5 g/kg) were preserved after acute and subchronic administration. The in vivo microdialysis revealed that aCaMKII T286A mice showed no dopamine (DA) response in the nucleus accumbens to acute or subchronic alcohol administration, but enhanced serotonin (5-HT) responses in the prefrontal cortex. The attenuated DA response in aCaMKII T286A mice was in line with altered c-Fos activation in the ventral tegmental area after acute and subchronic alcohol administration. In order to compare findings in mice with the human condition, we tested 23 single-nucleotide polymorphisms (SNPs) in the CAMK2A gene for their association with alcohol dependence in a population of 1333 male patients with severe alcohol dependence and 939 controls. We found seven significant associations between CAMK2A SNPs and alcohol dependence, one of which in an autophosphorylation-related area of the gene. Together, our data suggest aCaMKII autophosphorylation as a facilitating mechanism in the establishment of alcohol drinking behavior with changing the DA-5-HT balance as a putative mechanism.

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Section: Introductionmentioning

confidence: 99%

αCaMKII Autophosphorylation Controls the Establishment of Alcohol Drinking Behavior

Easton

Lucchesi

Lourdusamy

et al. 2013

Neuropsychopharmacol

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“…Recently, studies showed that CaMKIIs play an important role in cell apoptosis. They also reported that CaMKII, as a critical mediator of ethanolinduced apoptosis, switches to convert ethanol's short-lived Ca 2+ transient into a long-term effect on cellular activity (Garic et al 2011). Some study results indicate that CaMKII does not participate in the extrinsic cascade of apoptosis but is involved in the intrinsic (mitochondrial) pathway.…”

Section: Discussionmentioning

confidence: 96%

Increased Expression of Calcium/Calmodulin-Dependent Protein Kinase Type II Subunit Delta after Rat Traumatic Brain Injury

Zhang

Shan

et al. 2011

J Mol Neurosci

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Many cellular responses to Ca(2+) signals are mediated by Ca(2+)/calmodulin-dependent enzymes, among which is the Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). CaMKII was originally described in rat brain tissue. In rat brain, four different subunits of the kinase have been identified: α, β, γ, and δ. This study aims to investigate changes of CaMKIIδ after traumatic brain injury and its possible role. Rat traumatic brain injury (TBI) model was established by controlled cortical injury system. In the present study, we mainly investigated the expression and cellular localization of CaMKIIδ after traumatic brain injury. Western blot analysis revealed that CaMKIIδ was present in normal rat brain cortex. It gradually increased, reached a peak at the third day after TBI, and then decreased. Importantly, more CaMKIIδ was colocalized with neuron. In addition, Western blot detection showed that the third day postinjury was also the apoptosis peak indicated by the elevated expression of caspase-3.Importantly, immunohistochemistry analysis revealed that injury-induced expression of CaMKIIδ was colabeled by caspase-3 (apoptosis cells marker). Moreover, pretreatment with the CaMKII inhibitor (KN62) reduced the injury-induced activation of caspase-3. Noticeably, the CaMKII inhibitor KN-62 could reduce TBI-induced cell injury assessed with lesion volume and attenuate behavioral outcome evaluated by motor test. These data suggested that CaMKIIδ may be implicated in the apoptosis of neuron and the recovery of neurological outcomes. However, the inherent mechanisms remained unknown. Further studies are needed to confirm the exact role of CaMKIIδ after brain injury.

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“…In contrast, repeated alcohol administration enhances CaMKII activity in neurons and astrocytes ( Figure 1) [108,109] and increases phosphorylation rate [110]. Free choice alcohol drinking increased protein levels of CaMKII, but not CaMKII in the amygdala and NAc of mice [111].…”

Section: Alcoholmentioning

confidence: 98%

CaM Kinases: From Memories to Addiction

Müller

Quednow

Lourdusamy

et al. 2016

Trends in Pharmacological Sciences

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Drug addiction is a major psychiatric disorder with a neurobiological base that is still insufficiently understood. Initially, non-addicted, controlled drug consumption and drug instrumentalization are established. They comprise highly systematic behaviours acquired by learning and the establishment of drug memories. Ca 2+ /calmodulin-dependent protein kinases (CaMKs) are important Ca 2+ -sensors translating glutamatergic activation into synaptic plasticity during learning and memory formation. Here we review the role of CaMKs in the establishment of drugrelated behaviours in animal models and in humans. Converging evidence shows now that CaMKs are a crucial mechanism of how addictive drugs induce synaptic plasticity and establish various types of drug memories. Thereby, CaMKs are not only molecular relays for glutamatergic activity; they also directly control dopaminergic and serotonergic activity in the mesolimbic reward system. They can now be considered as major molecular pathways translating normal memory formation into establishment of drug memories and possibly transition to drug addiction. Keywords: Ca 2+/calmodulin-dependent protein kinase, drug dependence, addiction, psychostimulants, alcohol, opioids 3 Drug Use and AddictionDrug addiction is a major psychiatric disorder for which only limited therapies are currently available [1,2]. A striking criterion for drug abuse and addiction is that it severely threatens one's own and others well-being and health. As such, there is a persistent need to treat drug addiction effectively, and ideally reverse the behavioural repertoire of an affected individual back to normal.An important feature of drug addiction is that it develops from a behavioural repertoire, which is considered to be normal in many societies of the world: the controlled consumption and instrumentalization of psychoactive drugs [3,4].Establishing and maintaining controlled drug consumption is based on systematic learning and memory retrieval of distinct behaviours, related to drug seeking, preparation, and consumption in a specific context [5,6]. Thereby, information is encoded within different behavioural systems, which can be summarized as "drug memories" [5,[7][8][9] (Box 1). It is believed that an intensification of these memories together with a loss of impulse control (compulsivity) is responsible for the transition from controlled drug use to addiction [10][11][12]. Understanding how these drug memories are established and how they may take control over a normal behavioural repertoire should, therefore, allow to improve the prevention of addiction and to develop new and more effective treatments [13]. From Memories to Drug MemoriesIt was suggested that anatomical pathways, micro-morphological adaptations, as well as molecular mechanisms in the brain, overlap between normal learning and memory and drug memories [14][15][16]. A crucial player for memory formation in the brain is the glutamatergic system and its plasticity based on experience [17]. Addiction research considered glu...

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CaMKII activation is a novel effector of alcohol’s neurotoxicity in neural crest stem/progenitor cells

Cited by 48 publications

References 68 publications

αCaMKII Autophosphorylation Controls the Establishment of Alcohol Drinking Behavior

αCaMKII Autophosphorylation Controls the Establishment of Alcohol Drinking Behavior

Increased Expression of Calcium/Calmodulin-Dependent Protein Kinase Type II Subunit Delta after Rat Traumatic Brain Injury

CaM Kinases: From Memories to Addiction

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