Role of protein kinase C in agonist-induced desensitization of 5-HT₁A receptor coupling to calcium channels in F11 cells.

The 5-Hydroxytriptamine 1A receptor (5-HT1A) is expressed both as a pre- and post-synaptic receptor in neurons. The presynaptic receptor preferentially desensitizes compared to post-synaptic receptors, suggesting different underlying mechanisms of agonist-induced desensitization. Using F11 cells as a model of post-synaptic neurons, the present study examined the role of protein kinase C (PKC) and protein kinase A (PKA) in desensitization of the 5-HT1A-receptor by agonist.

Cytoplasmic mutant p53 increases Bcl-2 expression in estrogen receptor-positive breast cancer cells.

The Bcl-2 gene is positively regulated by estrogen (E2) primarily through E2-response elements in the coding region and a putative p53 negative regulatory element (NRE) containing a short upstream open reading frame (uORF). The ability of mutant p53 to repress or induce Bcl-2 expression is controversial. In this study E2-receptor positive (ER(+))/wild-type p53 MCF-7cells were transfected with p53Delta291, which lacks a nuclear localization signal or a DNA binding domain mutant, p53(173L).

Molecular determinants in the second intracellular loop of the 5-hydroxytryptamine-1A receptor for G-protein coupling.

This study provides the first comprehensive evidence that the second intracellular loop C-terminal domain (Ci2) is critical for receptor-G protein coupling to multiple responses. Although Ci2 is weakly conserved, its role in 5-hydroxytryptamine-1A (5-HT1A) receptor function was suggested by the selective loss of Gbetagamma-mediated signaling in the T149A-5-HT1A receptor mutant. More than 60 point mutant 5-HT1A receptors in the alpha-helical Ci2 sequence (143DYVNKRTPRR152) were generated.

Differential roles of nuclear and cytoplasmic cyclin-dependent kinase 5 in apoptotic and excitotoxic neuronal death.

Cyclin-dependent kinase 5 (cdk5) is a member of the cyclin-dependent kinase family whose activity is localized mainly to postmitotic neurons attributable to the selective expression of its activating partners p35 and p39. Deregulation of cdk5, as a result of calpain cleavage of p35 to a smaller p25 form, has been suggested to be a central component of neuronal death underlying numerous neurodegenerative diseases. However, the relevance of cdk5 in apoptotic death that relies on the mitochondrial pathway is unknown.

Coupling of 5-HT1A autoreceptors to inhibition of mitogen-activated protein kinase activation via G beta gamma subunit signaling.

The 5-HT1A receptor is expressed presynaptically as the primary somatodendritic autoreceptor on serotonergic raphe neurons, and postsynaptically in several brain regions. Signaling of the 5-HT1A autoreceptor was studied in RN46A cells, a model of serotonergic raphe neurons that express endogenous 5-HT1A receptors. In undifferentiated RN46A cells stably transfected with the wild-type 5-HT1A receptor, 5-HT1A receptor activation inhibited forskolin-induced cyclic adenosine monophosphate (cAMP) formation (by 50%), increased [Ca2+]i, and induced a novel inhibition (up to 60%) of phospho-p42/p44-mitogen-activated protein kinase (MAPK).

The proapoptotic gene SIVA is a direct transcriptional target for the tumor suppressors p53 and E2F1.

The p53 tumor suppressor gene is believed to play an important role in neuronal cell death in acute neurological disease and in neurodegeneration. The p53 signaling cascade is complex, and the mechanism by which p53 induces apoptosis is cell type-dependent. Using DNA microarray analysis, we have found a striking induction of the proapoptotic gene, SIVA.