INT118678

Context Info Confidence 0.82 First Reported 2004 Last Reported 2010 Negated 0 Speculated 0 Reported most in Abstract Documents 22 Total Number 23 Disease Relevance 9.40 Pain Relevance 10.70

signal transduction (Camk4) nucleocytoplasmic transport (Camk4) nucleus (Camk4) kinase activity (Camk4) cytoplasm (Camk4)

Anatomy Link Frequency hippocampus 4 neuronal 1 neurons 1 brain 1 caudate putamen 1 Camk4 (Mus musculus)

Pain Link Frequency Relevance Heat addiction 12 99.90 Hippocampus 60 99.84 Morphine 42 99.82 fluoxetine 31 99.04 Opioid 19 98.16 Somatosensory cortex 6 98.12 psychological dependence 5 97.84 Anterior cingulate cortex 244 97.24 mu opioid receptor 1 97.12 long-term potentiation 166 96.80

Disease Link Frequency Relevance Heat Drug Dependence 11 99.90 Stress 61 99.30 Urological Neuroanatomy 14 99.12 Targeted Disruption 443 98.20 Repression 8 97.12 Anxiety Disorder 561 93.80 Depression 17 88.60 Neurodegenerative Disease 15 85.12 Sprains And Strains 28 84.56 Hypertrophy 3 74.20

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Thus CaMKIV mediated phosphorylation of CREB may be a major mediator of this consolidation, in part through enhancement of local slow delta oscillations during NREM sleep.

Phosphorylation (phosphorylation) of CaMKIV

1) Confidence 0.82 Published 2010 Journal Mol Brain Section Body Doc Link PMC2888801 Disease Relevance 0.43 Pain Relevance 0.19

CaMKIV phosphorylates CREB at a particular residue, serine 133 (Ser133), and phosphorylation of Ser133 is required for CREB-mediated transcription [29].

Phosphorylation (phosphorylates) of CaMKIV

2) Confidence 0.82 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2830479 Disease Relevance 0.05 Pain Relevance 0.18

CaMKIV phosphorylates CREB and the phosphorylation is terminated by calcineurin, possibly through direct CREB dephosphorylation or through activation of the downstream protein phosphatase 1 [19].

Phosphorylation (phosphorylation) of CaMKIV

3) Confidence 0.82 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2830479 Disease Relevance 0.40 Pain Relevance 0.11

Second, it has been demonstrated that CaMKIV phosphorylates and regulates the function of synaptic proteins including the actin binding protein synapsin I [35] and the microtubule regulator Stathmin [36].

Phosphorylation (phosphorylates) of CaMKIV

4) Confidence 0.82 Published 2010 Journal Mol Brain Section Body Doc Link PMC2949850 Disease Relevance 0.47 Pain Relevance 0.57

The nuclear location of CaMKIV, its ability to phosphorylate CREB and its broad expression throughout forebrains areas suggests that CaMKIV may play an important role in higher brain function.

Phosphorylation (phosphorylate) of CaMKIV in brain

5) Confidence 0.82 Published 2005 Journal Mol Pain Section Body Doc Link PMC1208947 Disease Relevance 0.70 Pain Relevance 0.34

CaMKIV is a serine-threonine kinase and is activated by a combination of elevated intracellular Ca2+ and CaMK kinase during neuronal activity [for review, see [25] and phosphorylates CREB [26,27]].

Phosphorylation (phosphorylates) of CaMKIV in neuronal

6) Confidence 0.82 Published 2010 Journal Mol Brain Section Body Doc Link PMC2888801 Disease Relevance 0.05 Pain Relevance 0.03

It has been well established that the cyclic AMP-responsive element binding protein (CREB) is a major transcription factor associated with long-term memory [12,13], and calcium-calmodulin-dependent protein kinase IV (CaMKIV) plays an essential role in activity-dependent CREB phosphorylation [14-16].

Phosphorylation (phosphorylation) of CaMKIV

7) Confidence 0.81 Published 2010 Journal Mol Brain Section Body Doc Link PMC2949850 Disease Relevance 0.20 Pain Relevance 0.81

The CMS procedure inhibited hippocampal protein kinase A (PKA) activity, extracellular signal-regulated kinases (ERK1/2), and calcium/calmodulin-dependent protein kinase IV (CaMKIV) phosphorylation in AQP4(+/+) and AQP4(-/-) mice.

Phosphorylation (phosphorylation) of calcium/calmodulin-dependent protein kinase IV associated with stress

8) Confidence 0.80 Published 2009 Journal Neuropsychopharmacology Section Abstract Doc Link 18923397 Disease Relevance 1.38 Pain Relevance 0.66

However, fluoxetine restored CMS-induced inhibition of hippocampal CaMKIV phosphorylation in AQP4(+/+) mice but failed in AQP4(-/-) mice.

Phosphorylation (phosphorylation) of CaMKIV associated with stress and fluoxetine

9) Confidence 0.78 Published 2009 Journal Neuropsychopharmacology Section Abstract Doc Link 18923397 Disease Relevance 1.29 Pain Relevance 0.73

This is the first evidence to suggest that the increased CREB phosphorylation via CaMKIV signal pathway in hippocampus is relevant to opioids psychological dependence.

Phosphorylation (phosphorylation) of CaMKIV in hippocampus associated with psychological dependence, hippocampus and opioid

10) Confidence 0.78 Published 2004 Journal Brain Res. Section Abstract Doc Link 15451364 Disease Relevance 0.10 Pain Relevance 0.55

Thus, it appears that CaMKIV, a key upstream molecule which phosphorylates CREB [26], can modulate the expression of slow delta oscillations as a consequence of learning.

Phosphorylation (phosphorylates) of CaMKIV

11) Confidence 0.71 Published 2010 Journal Mol Brain Section Body Doc Link PMC2888801 Disease Relevance 0.53 Pain Relevance 0.21

CaMKIV plays a role in the activity-dependent phosphorylation of CREB, which regulates the expression of genes involved in neuroplasticity [24], learning and memory [25], [26], and emotional behaviors [27], [28].

Phosphorylation (phosphorylation) of CaMKIV

12) Confidence 0.71 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2830479 Disease Relevance 0.05 Pain Relevance 0.19

cAMP response-element binding protein (CREB), a transcription factor involved in learning, memory and drug addiction, is phosphorylated by calcium-calmodulin-dependent protein kinase IV (CaMKIV).

Phosphorylation (phosphorylated) of CaMKIV associated with drug dependence and addiction

13) Confidence 0.71 Published 2006 Journal Eur. J. Neurosci. Section Abstract Doc Link 16630062 Disease Relevance 0.57 Pain Relevance 0.89

cAMP response-element binding protein (CREB), a transcription factor involved in learning, memory and drug addiction, is phosphorylated by calcium-calmodulin-dependent protein kinase IV (CaMKIV).

Phosphorylation (phosphorylated) of kinase IV associated with drug dependence and addiction

14) Confidence 0.71 Published 2006 Journal Eur. J. Neurosci. Section Abstract Doc Link 16630062 Disease Relevance 0.57 Pain Relevance 0.89

The CMS procedure inhibited hippocampal protein kinase A (PKA) activity, extracellular signal-regulated kinases (ERK1/2), and calcium/calmodulin-dependent protein kinase IV (CaMKIV) phosphorylation in AQP4(+/+) and AQP4(-/-) mice.

Phosphorylation (phosphorylation) of CaMKIV associated with stress

15) Confidence 0.68 Published 2009 Journal Neuropsychopharmacology Section Abstract Doc Link 18923397 Disease Relevance 1.36 Pain Relevance 0.66

F9203, which could not induce CPP, failed to increase the CREB phosphorylation and the colocalization of P-CREB with CaMKIV both in hippocampus from CPP mice and in cultured hippocampal neurons.

Phosphorylation (phosphorylation) of CaMKIV in neurons associated with hippocampus

16) Confidence 0.60 Published 2004 Journal Brain Res. Section Abstract Doc Link 15451364 Disease Relevance 0 Pain Relevance 0.58

Calcineurin directly dephosphorylates and inactivates CaMKIV [18].

Phosphorylation (dephosphorylates) of CaMKIV

17) Confidence 0.55 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2830479 Disease Relevance 0.41 Pain Relevance 0

To better understand the role of CREB in opioids dependence and underlying signal pathways, we compared the effects of three ohmfentanyl stereoisomers ((-)-cis-(3R,4S,2'R) OMF (F9202), (+)-cis-(3R,4S,2'S) OMF (F9204), (-)-cis-(3S,4S,2'R) OMF (F9203)) and morphine on CREB phosphorylation and the expression of Ca2+/calmodulin-dependent protein kinase IV (CaMKIV) in hippocampus derived from mice which displayed conditioned place preference (CPP) behavior by Western blot, and immunohistochemistry analyses.

Phosphorylation (phosphorylation) of CaMKIV in hippocampus associated with addiction, hippocampus, opioid and morphine

18) Confidence 0.52 Published 2004 Journal Brain Res. Section Abstract Doc Link 15451364 Disease Relevance 0 Pain Relevance 0.61

To better understand the role of CREB in opioids dependence and underlying signal pathways, we compared the effects of three ohmfentanyl stereoisomers ((-)-cis-(3R,4S,2'R) OMF (F9202), (+)-cis-(3R,4S,2'S) OMF (F9204), (-)-cis-(3S,4S,2'R) OMF (F9203)) and morphine on CREB phosphorylation and the expression of Ca2+/calmodulin-dependent protein kinase IV (CaMKIV) in hippocampus derived from mice which displayed conditioned place preference (CPP) behavior by Western blot, and immunohistochemistry analyses.

Phosphorylation (phosphorylation) of calmodulin-dependent protein kinase IV in hippocampus associated with addiction, hippocampus, opioid and morphine

19) Confidence 0.52 Published 2004 Journal Brain Res. Section Abstract Doc Link 15451364 Disease Relevance 0 Pain Relevance 0.60

The results showed that F9202, F9204 or morphine, which could induce CPP, enhanced CREB phosphorylation and the expression of CaMKIV in hippocampus from CPP mice without affecting total CREB protein level.

Phosphorylation (phosphorylation) of CaMKIV in hippocampus associated with hippocampus and morphine

20) Confidence 0.52 Published 2004 Journal Brain Res. Section Abstract Doc Link 15451364 Disease Relevance 0 Pain Relevance 0.71

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