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Insulin-like growth factor-1 regulat...

Gao, Lei.

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Insulin-like growth factor-1 regulation of Ca(v)1.3 L-type calcium channels.

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
正題名/作者:	Insulin-like growth factor-1 regulation of Ca(v)1.3 L-type calcium channels./
作者:	Gao, Lei.
面頁冊數:	218 p.
附註:	Adviser: John Marshall.
Contained By:	Dissertation Abstracts International67-08B.
標題:	Biology, Neuroscience. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3227832
ISBN:	9780542818981

Insulin-like growth factor-1 regulation of Ca(v)1.3 L-type calcium channels.
Gao, Lei.

Insulin-like growth factor-1 regulation of Ca(v)1.3 L-type calcium channels. - 218 p.

Adviser: John Marshall.

Thesis (Ph.D.)--Brown University, 2006.

Insulin-like growth factor-1 (IGF-1) has been shown to potentiate neuronal Cav1.2 (alpha1C) L-type calcium channels in cerebellar granule neurons and SH-SY5Y cells through a PI 3-kinase and src-dependent pathway. The ability of IGF-1 to enhance neuronal survival is partially dependent on its modulation on Cav1.2. However, the relationship between IGF-1 and Ca1v1.3 (alpha1D), a homologous L-type channel of Ca v1.2, is still unknown. Here, I provide the evidence that IGF-1 can also acutely potentiate Cav1.3 calcium channel currents and that this potentiation is dependent on the activities of phospholipase C (PLC), IP3-sensitive internal calcium stores, and Ca2+/CaM-dependent protein kinase II (CaMKII). Use of specific pharmacological inhibitors to any of these signaling components, or expression of a kinase-deficient mutation of CaMKII, resulted in complete block of the IGF-1 response of Cav1.3. Moreover, expression of a constitutively-active form of CaMKII bypassed the need for IGF-1 and mimicked the production of IGF-1-induced Cav1.3 potentiation.

ISBN: 9780542818981Subjects--Topical Terms:

1017680
Biology, Neuroscience.

Insulin-like growth factor-1 regulation of Ca(v)1.3 L-type calcium channels.
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100 1 $a Gao, Lei. $3 1287129
245 1 0 $a Insulin-like growth factor-1 regulation of Ca(v)1.3 L-type calcium channels.
300 $a 218 p.
500 $a Adviser: John Marshall.
500 $a Source: Dissertation Abstracts International, Volume: 67-08, Section: B, page: 4363.
502 $a Thesis (Ph.D.)--Brown University, 2006.
520 $a Insulin-like growth factor-1 (IGF-1) has been shown to potentiate neuronal Cav1.2 (alpha1C) L-type calcium channels in cerebellar granule neurons and SH-SY5Y cells through a PI 3-kinase and src-dependent pathway. The ability of IGF-1 to enhance neuronal survival is partially dependent on its modulation on Cav1.2. However, the relationship between IGF-1 and Ca1v1.3 (alpha1D), a homologous L-type channel of Ca v1.2, is still unknown. Here, I provide the evidence that IGF-1 can also acutely potentiate Cav1.3 calcium channel currents and that this potentiation is dependent on the activities of phospholipase C (PLC), IP3-sensitive internal calcium stores, and Ca2+/CaM-dependent protein kinase II (CaMKII). Use of specific pharmacological inhibitors to any of these signaling components, or expression of a kinase-deficient mutation of CaMKII, resulted in complete block of the IGF-1 response of Cav1.3. Moreover, expression of a constitutively-active form of CaMKII bypassed the need for IGF-1 and mimicked the production of IGF-1-induced Cav1.3 potentiation.
520 $a Specifically, a single serine residue (S1486), which is within a CaMKII consensus site in the carboxyl-terminal EF hand region is found to be critical for IGF-1-induced potentiation of Cav1.3. S1486A mutated Ca v1.3 channels were no longer able to respond to IGF-1. In addition, phospho-mimic S1486D-Cav1.3 channels behaved like the potentiated wild-type Cav1.3 channel, generating relatively larger current densities at more negative membrane potentials.
520 $a Biophysically, Cav1.3 potentiation arises from increased activation of the channel at hyperpolarized membrane potentials by IGF-1. Furthermore, via CaMKII and phosphorylation of S1486, potentiated Cav1.3 channels displayed an accelerated rate of recovery from calcium-dependent inactivation. As a result, IGF-1 can reduce the cumulative inactivation of Cav1.3, which was displayed by the channel during spike-like "action potential" trains.
520 $a Functionally, in cortical neurons, enhancement of pCREB levels in response to IGF-1 is partially dependent on activities of Cav1.3 calcium channels. IGF-1 modulation of Cav1.3 further increases pCREB. Moreover, an adaptor protein Shank is critical in terms of associating IP3-sensitive calcium stores with surface Cav1.3 channels. Disrupting the interactions of Shank either to Cav1.3 or to IP3R via Homer impaired the IGF-I-Cav1.3-dependent pCREB increase.
520 $a Overall, these results define a novel signaling pathway underlying the acute modulation of Cav1.3 channels by IGF-1-intracellular Ca 2+-CaMKII signaling cascade, and describe the initial short- and long-term effects. This modulation may influence many critical cellular functions such as neuronal survival, firing activities, and synaptic efficacy.
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