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RXMCDM: ½ð±Ò+3, ¶àлӦÖú£¡ 2014-03-13 11:25:52
ygy19901025: ½ð±Ò+100, ·­ÒëEPI+1, ¡ï¡ï¡ï¡ï¡ï×î¼Ñ´ð°¸ 2014-03-13 12:37:36
Abstract
ÕªÒª
Glycogen synthase kinase-3 (GSK-3) plays a critical role in neuronal apoptosis.
ÌÇÔ­ºÏ³Éø¼¤Ã¸-3ÔÚÉñ¾­ÔªµòÍöÖÐÆðµ½Á˹ؼü×÷Óá£
The two mammalian isoforms of the kinase, GSK-3¦Á and GSK-3¦Â, are inhibited by phosphorylation at Ser-21 and Ser-9, respectively.
ÕâÒ»¼¤Ã¸ÔÚ²¸È鶯ÎïÖеÄÁ½ÖÖͬ¹¤Ã¸£¨²Â²â£¬isoenzyme£©£¬GSK--3¦ÁºÍGSK-3¦Â£¬»á·Ö±ð±»Ser-21ºÍSer-9µÄÁ×ËữÐÞÊÎËùÒÖÖÆ¡£
Depolarization, which is vital for neuronal survival, causes both an increase in Ser-21/9 phosphorylation and an inhibition of GSK-3¦Á/¦Â.
¶ÔÓÚÉñ¾­ÔªµÄÉú´æÖÁ¹ØÖØÒªµÄÈ¥¼«»¯×÷ÓûᵼÖÂSer-21/9µÄÁ×ËữˮƽµÄÉÏÉý£¬²¢ÒÖÖÆGSK-3¦Á/¦ÂµÄ»îÐÔ¡£
However, the role of GSK-3 phosphorylation in depolarization-dependent neuron survival and the signaling pathway contributing to GSK-3 phosphorylation during depolarization remain largely unknown.
È»¶ø£¬GSK-3Á×ËữÔÚÒÀÀµÓÚÈ¥¼«»¯×÷ÓõÄÉñ¾­ÔªÉú´æÖеÄ×÷Óã¬ÒÔ¼°ÐźÅͨ·ÔÚÈ¥¼«»¯¹ý³ÌÖжÔGSK-3Á×ËữµÄ×÷ÓÃÔںܴó³Ì¶ÈÉÏ»¹²»µÃ¶øÖª¡£
Using several approaches, we showed that both isoforms of GSK-3 are important for mediating neuronal apoptosis.
ͨ¹ý¼¸ÖÖз½·¨£¬ÎÒÃÇ·¢ÏÖGSK-3µÄÁ½¸öͬ¹¤Ã¸Ôڽ鵼Éñ¾­ÔªµòÍöÖÐÆðµ½ÁËÖØÒªµÄ×÷Óá£
Nonphosphorylatable GSK-3¦Á/¦Â mutants (S21A/S9A) promoted apoptosis, whereas a peptide encompassing Ser-9 of GSK-3¦Â protected neurons in a phosphorylation-dependent manner; these results indicate a critical role for Ser-21/9 phosphorylation on depolarization-dependent neuron survival.
²»¿ÉÁ×ËữµÄGSK-3¦Á/¦ÂÍ»±äÌ壨S21A/S9A£©´Ù½øÁ˵òÍö£¬È»¶øÒ»¸ö°üΧÁËGSK-3¦ÂµÄSer9µÄëÄÁ´ÔòÒÔÒ»ÖÖÒÀÀµÓÚÁ×ËữµÄ·½Ê½¶ÔÉñ¾­ÔªÆðµ½Á˱£»¤×÷Óã»ÕâЩ½á¹ûÏÔʾ£¬Ser-21/9µÄÁ×ËữÔÚÒÀÀµÓÚÈ¥¼«»¯×÷ÓõÄÉñ¾­ÔªÉú´æÖÐÆðµ½ÁËÖÁ¹ØÖØÒªµÄ×÷Óá£
We found that Ser-21/9 phosphorylation of GSK-3 was mediated by Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) but not by Akt/PKB, PKA, or p90(RSK).
ÎÒÃÇ·¢ÏÖGSK-3µÄSer-21/9Á×ËữÊÇÓÉÒÀÀµÓÚ¸ÆÀë×Ó/¸Æµ÷µ°°×µÄµ°°×¼¤Ã¸II£¨CaMKII£©£¬¶ø·ÇAkt/PKB,PKA»òÕßp90(RSK)Ëù½éµ¼µÄ¡£
CaMKII associated with and phosphorylated GSK-3¦Á/¦Â.
CaMKIIÓëÁ×ËữµÄGSK-3¦Á/¦ÂÏàÁ¬£¨Õâ¸öandÊÇʲôÒâ˼£¬´æÒÉ£©¡£
Furthermore, the pro-survival effect of CaMKII was mediated by GSK-3 phosphorylation and inactivation.
´ËÍ⣬CaMKIIµÄ´Ù´æ»îЧӦ£¨pro-survival effect£¬Ò²ÐíÓиüÌùÇеÄÊõÓÊÇÓÉGSK-3Á×ËữºÍʧ»îËù½éµ¼µÄ¡£
These findings identify a novel Ca(2+)/calmodulin/CaMKII/GSK-3 pathway that couples depolarization to neuronal survival.
ÕâЩ·¢ÏÖÈ·¶¨ÁËÒ»ÌõеĸÆÀë×Ó/¸Æµ÷µ°°×/CaMKII/GSK-3;¾¶£¬ÕâÌõ;¾¶ÊÇÓëÉñ¾­ÔªÉú´æµÄÈ¥¼«»¯×÷ÓÃÏàżÁªµÄ¡£
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