Inhibition of 5-HT1A receptor-dependent cell survival by cAMP/protein kinase A: role of protein phosphatase 2A and Bax.
Serotonergic 5-HT(1A) receptor signaling leading to nuclear factor-kappaB (NF-kappaB) activation appears to be critical for cell survival. Adenylyl cyclase and protein kinase A (AC/PKA) are effectors of the 5-HT(1A) receptor that are inhibited by Galpha(i) subunits. Conversely, Gbetagamma(i) subunits downstream from the 5-HT(1A) receptor participate in the activation of extracellular signal-regulated kinases (ERK1/2), phosphatidylinositol 3-kinase (PI3K), Akt, and NF-kappaB. To model the contribution of pro- and antiapoptotic signaling cascades downstream of activated 5-HT(1A) receptor in cell survival, Chinese hamster ovarian (CHO) cells were employed that exogenously overexpress 5-HT(1A) receptors. Stimulation with the 5-HT(1A) receptor agonist 8-OH-DPAT and pharmacological agonists of AC induced PKA and protein phosphatase 2A (PP2A) activity, which in turn inhibited: Akt activity, IkappaBalpha degradation, nuclear translocation of NF-kappaB, and expression of X-linked inhibitor of apoptosis protein (XIAP/BIRC4). Pharmacological inhibition of PP2A with calyculin A potentiated Akt activity while attenuating ERK1/2 signaling via increased inhibitory phosphorylation of Raf (pSer259). In contrast, increased cAMP levels enhanced Bax translocation to the mitochondria, resulting in the release of cytochrome c, caspase-3 activation, and apoptosis induction. Our data suggest a central role of cAMP/PKA-dependent PP2A in shifting the homeostasis of intracellular signaling downstream of activated 5-HT(1A) receptor toward cell death in biological systems linked to neuropsychiatric disorders.
Hsiung
Shu-chi
SC
Division of Neuroscience, New York State Psychiatric Institute, New York, New York, USA.
Tin
Adrianne
A
Tamir
Hadassah
H
Franke
Thomas F
TF
Liu
Kuo-peing
KP
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D016466:CHO Cells; D002470:Cell Survival; D006224:Cricetinae; D003412:Cricetulus; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D006801:Humans; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
D051028:bcl-2-Associated X Protein; D044282:Receptor, Serotonin, 5-HT1A; D017868:Cyclic AMP-Dependent Protein Kinases; D054648:Protein Phosphatase 2