Abstract
Moderate increases of intracellular Ca2+ concentration ([Ca2+]i), induced by either the activation of tropomyosin receptor kinase (Trk) receptors for neurotrophins or by neuronal activity, regulate different intracellular pathways and neuronal survival. In the present report we demonstrate that glial cell line-derived neurotrophic factor (GDNF) treatment also induces [Ca2+]i elevation by mobilizing this cation from internal stores. The effects of [Ca2+]i increase after membrane depolarization are mainly mediated by calmodulin (CaM). However, the way in which CaM exerts its effects after tyrosine kinase receptor activation remains poorly characterized. It has been reported that phosphatidylinositol 3-kinase (PI 3-kinase) and its downstream target protein kinase B (PKB) play a central role in cell survival induced by neurotrophic factors; in fact, GDNF promotes neuronal survival through the activation of the PI 3-kinase/PKB pathway. We show that CaM antagonists inhibit PI 3-kinase and PKB activation as well as motoneuron survival induced by GDNF. We also demonstrate that endogenous Ca2+/CaM associates with the 85-kDa regulatory subunit of PI 3-kinase (p85). We conclude that changes of [Ca2+]i, induced by GDNF, promote neuronal survival through a mechanism that involves a direct regulation of PI 3-kinase activation by CaM thus suggesting a central role for Ca2+ and CaM in the signaling cascade for neuronal survival mediated by neurotrophic factors.
Highlights
Moderate increases of intracellular Ca2؉ concentration ([Ca2؉]i), induced by either the activation of tropomyosin receptor kinase (Trk) receptors for neurotrophins or by neuronal activity, regulate different intracellular pathways and neuronal survival
It has been reported that phosphatidylinositol 3-kinase (PI 3-kinase) and its downstream target protein kinase B (PKB) play a central role in cell survival induced by neurotrophic factors; glial cell line-derived neurotrophic factor (GDNF) promotes neuronal survival through the activation of the PI 3-kinase/PKB pathway
We conclude that changes of [Ca2؉]i, induced by GDNF, promote neuronal survival through a mechanism that involves a direct regulation of PI 3-kinase activation by CaM suggesting a central role for Ca2؉ and CaM in the signaling cascade for neuronal survival mediated by neurotrophic factors
Summary
Moderate increases of intracellular Ca2؉ concentration ([Ca2؉]i), induced by either the activation of tropomyosin receptor kinase (Trk) receptors for neurotrophins or by neuronal activity, regulate different intracellular pathways and neuronal survival. PKB activation mediates cell survival after neurotrophic factor treatment and the activation of PI 3-kinase (10, 18 –20). To investigate the role of Ca2ϩ and CaM on GDNF-induced PI 3-kinase/PKB activation tration; CaM, calmodulin; PI, phosphatidylinositol; GDNF, glial cell line-derived neurotrophic factor; MTN, spinal cord motoneurons; PKB, Ser/Thr protein kinase B; ERK, extracellular regulated kinase; MAP, mitogen-activated kinase; Trk, tropomyosin receptor kinase; GFL, GDNF-family ligands; GFR, GDNF family receptors; EGFP, enhanced green fluorescent protein; BAPTA-AM, 1,2-bis(2-aminophenoxy)ethylene N,N,NЈ,NЈ-tetraacetic acid acetomethyl ester; AFU, arbitrary fluorescence units; P-Tyr, antiphosphotyrosine; PBS, phosphate-buffered saline; MEX, muscle extract; NE, absence of MEX; E, embryonic day; TFP, trifluoperazine dimaleate; TG, thapsigargin; AFU, arbitrary fluorescence units.
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