CaMKⅡ:A molecular switch of synaptic plasticity / 中国药理学通报

Calcium/calmodulin-dependent protein kinase Ⅱ(CaMKⅡ),which is an important protein kinase involved in learning and memory,is found in most tissues,but it is present in especially high concentrations in neurons.The relatively high expression of CaMKⅡin nervous system suggests it plays an im-portant role in the function of nervous system.This paper re-views the research development of the molecular structure of CaMKⅡ and its autophosphorylation,subcellular localization and its role in synaptic plasticity.

Transducción de la señal, pivote de la integración neurobiológica de la memoria: Una propuesta diferente a la tradicional hipótesis del sistema colinérgico / Signal transduction, pillar of the neurobiological integration of memory: An alternative view to the cholinergic hypothesis

Los procesos neurofisiológicos, bioquímicos y moleculares descritos en la integración de la memoria, más que estar relacionados con la actividad colinérgica involucran fundamentalmente a neurotransmisores como la serotonina y el glutamato, así como a diversos canales iónicos como los del calcio y los del potasio. De hecho, los receptores de estos neurotransmisores están ligados directamente con la activación de la potenciación a largo plazo (LTP), mecanismo que contribuye a la preservación de la memoria. De esta forma que la activación del receptor 5HT desencadena una señal de transducción que al influenciar bioquímicamente al núcleo produce diversos cambios presinápticos con los que se expulsa al magnesio del área postsináptica, despolarizando a la neurona y activando simultáneamente a los receptores N metilD Aspartato dependientes (NMDAR), contribuyendo en esta forma a perpetuar el mecanismo de LTP en sus distintas fases: LTP1 que depende de la activación de proteincinasas; LTP2 ligada con la traslación genética; y LTP3 relacionada con la transcripción. A este poderoso mecanismo de activación neuronal, se contrapone el fenómeno de depresión a largo plazo (LTD), que se inicia cuando la neurona pre sináptica activa al inhibidor 1 en el momento en que detecta una reducción en el influjo de calcio, promoviendo en esta forma la defosforilación de una proteincinasa tipo II calcio calmodulin dependiente, lo que detiene el desarrollo del proceso de autofosforilación y con ello, el mecanismo de LTP. No obstante lo difundido de la hipótesis colinérgica en la enfermedad de Alzheimer, la integración de la memoria depende fundamentalmente de la intervención de otros sistemas de neurotransmisión como lo son el serotonérgico y el glutamatérgico, los que no han sido debidamente considerados en el tratamiento de esta enfermedad; sin embargo más allá de estos sistemas, se encuentran los mecanismos de autofosforilación de distintas proteincinasas cuyo control, además de repercutir sobre la expresión genética, podría restituir algunos de los trastornos que afectan la función cognoscitiva.

Neurophysiological, biochemical and molecular processes described in the integration of memory are closely related with neurotransmitters such as glutamate and serotonin (5HT) and with the function of calcium and potassium ion channels more than with cholinergic activity. In fact, glutamate and 5 HT receptors are closely related with Long-Term Potentiation (LTP) processes, the mechanism by which memory is preserved throughout time. That is, the activation of the 5 HT4 receptor triggers a transduction signal that after influencing nuclear cell activity, provokes several presynaptic changes, which leads to the displacement of magnesium from the postsynaptic area depolarizing the neuron and leading to the activation of N methyl -D-aspartate receptors (NMDA). As a whole, this process contributes to the support and perpetuation of LTP, which consists of the following processes: LTP1 that depends on protein kinase activity; LTP2 linked to translation of genes; and LTP3 closely related to genes transcription. On the opposite side but in perfect balance, we find the mechanism of Long Term depression (LTD), which is triggered instead when the Ca++ flow decreases in the presynaptic neuron activating the inhibitor 1 enzyme that promotes the dephosphorylation of a calmodulin dependent protein kinase II and as a result, the inhibition of autophosphorylation and consequently of LTP too. Despite the widespread dissemination of the cholinergic hypothesis in Alzheimer's disease, memory build up rather than involving acetylcholine essentially depends on the participation of other neurotransmitters such as 5 HT and glutamate, which have not been adequately considered in the treatment of this disease. However, beyond neurotransmission, it is the cellular mechanism of autophosphorylation of several protein kinases, the process susceptible of being activated or controlled by the action of distinct substances. In such a case, it would be possible to exert some influence on gene expression improving perhaps, some of the physiopathological deficits that characterize memory disruption.

Effect of Articular Immobilization - Induced Hindlimb Skeletal Muscle Atrophy on Autophosphorylation of Tyrosine Kinase of the Insulin Receptor in Rats / 대한정형외과학회잡지

The purpose of this study was to investigate the effects of articular immobilization-induced hindlimb skeletal muscle atrophy on the autophosphorylation of the insulin receptor tyrosine kinase in rats. Rats were divided control, and knee and ankle joint immobilized groups. The experiments were performed on the 3rd, 7th, and 21st day after the immobilization. immobilization was induced by k-wire fixation in knee and ankle joint. The ratio of soleus muscle weight to body weight was decreased in proportion to the duration of the immobilization. The glycogen content of the soleus muscle was decreased significantly (p<0.01) at the 7th day, but this value was recovered to 65% of control at the 21st day after the immobilization. The insulin bindings at various concentrations of insulin to wheat-germ agglutinin purified insulin receptor from red gastrocnemius muscle at the 7th day after immobilization were not changed compared to control. The autophosphorylation of the insulin receptor tyrosine kinase with 10-8 and 10-7 M insulin concentration at the 7th day after immobilization was decreased compared to control. In conclusion, above results showed that insulin resistance of immobilized rat hindlimb skeletal muscle was arised from defect of autophosphorylation of the insulin receptor tyrosine kinase in part.

Nucleotide sequences of a cDNA coding for rat hck tyrosine kinase and characterization of its gene product.

The hck gene is member of src family of non-receptor type tyrosine kinases. Here we report the nucleotide sequence of the rat hck eDNA of 1.94 kb. The nuclcotide sequence shows an open reading frame coding for a polypeptide of 503 amino acids. A vector expressing a fusion protein of glutathione-S-transferase with 82 amino acids of the N-terminal region of hck (from amino acids 32 to 113) was constructed, Using this bacterially expressed fusion protein antibodies were prepared which recognize the cellular hck gene product. These antibodies identified, by immunoblotting, two polypeptides of 56 and 59 kDa in rat spleen where hck transcripts are present at high level. Immunoprecipitated hck polypeptides were enzymatically active and were autophosphorylated in the presence of ATP and Mg2+. 1mmunoprecipitated hck could phosphorylate exogenous substrates. Treatment of immunoprecipitated hck by a purified protein tyrosine phosphatase decreased its enzymatic acitivity. Our results suggest that the enzymatic activity of hck tyrosine kinase is regulated by phosphorylation and dephosphorylation.