Dokument

Summary:
Pituitary adenylate cyclase-activating polypeptide (PACAP)-mediated activation of its G protein-coupled receptor PAC1 results in activation of the two G proteins Gs and Gq to alter second messenger generation and gene transcription in the nervous system, important for homeostatic responses to stress and injury. PAC1 occurs in different splice variants of the third intracellular loop, designated PAC1null, hop or hip, affecting second messenger generation as shown in non-neural cells. At the splanchnico-adrenomedullary synapse, PACAP is required for prolonged catecholamine secretion from chromaffin cells to restore homeostasis during prolonged periods of stress. In the central nervous system, PACAP is neuroprotective in neurodegenerative conditions associated with e.g., stroke. In the present study, PAC1 splice variant-specific second messenger production and activation of homeostatic responses were investigated in neuroendocrine and neural cells. Heterologous expression of the major PAC1 splice variant of adrenomedullary chromaffin cells, PAC1hop, in PC12-G cells reconstituted a PACAP-mediated Ca2+ and prolonged secretory response similar to the one observed in primary chromaffin cells. The Ca2+ response mediated by PAC1null was somewhat smaller and PAC1hip failed to couple to Ca2+. Neither variant conferred prolonged catecholamine release, suggesting that expression of the hop cassette in the third intracellular loop of the receptor is required for sustained catecholamine release from neuroendocrine cells. In NG108-15 cells, heterologous expression of the PAC1hop, null and hip receptor conferred PACAP-mediated intracellular cAMP generation, while elevation of [Ca2+]i occurred efficiently in PAC1hop- and to a lesser extent in PAC1null-expressing cells. Expression of PAC1hip did not confer an intracellular Ca2+ response, indicating that PAC1hop is the receptor variant most efficiently coupled to combinatorial signaling through cAMP and Ca2+. PAC1hop-mediated signaling activated the mitogen-activated protein kinases (MAPK) extracellular signal-regulated kinases 1 and 2 (ERK1/2). Signaling to ERK proceeded through cAMP independently of the cAMP dependent protein kinase (PKA). PACAP induced transcription of the gene encoding the putative neuroprotectant stanniocalcin 1 (STC1), which has previously been implicated in neuronal resistance to hypoxic/ ischemic insult; gene induction proceeded through ERK but not PKA. Cyclic AMP generation by forskolin did not activate ERK in NG108-15 cells, but rather induced STC1 mRNA elevation through the canonical PKA dependent pathway. This suggests that activation of non-canonical cAMP signaling, mediating ERK-dependent gene induction, requires additional signaling through Ca2+ via PAC1hop in these cells. Primary rat cortical neurons expressed predominantly the PAC1hop and null variants. Exposure of cortical neurons to PACAP resulted in elevation of the two second messengers cAMP and Ca2+, activation of ERK1/2, and induction of STC1 gene transcription. PACAP-mediated ERK activation proceeded through cAMP but not PKA, and STC1 was induced via ERK but not PKA. Pharmacological stimulation of adenylate cyclases by forskolin also resulted in increased ERK phosphorylation and STC1 mRNA elevation independently of PKA. These results indicate that cAMP production alone is sufficient to activate ERK in differentiated cortical neurons, unlike in the less differentiated NG108-15 cell line. Induction of another PACAP target gene, brain-derived neurotrophic factor (BDNF), occurred through the canonical cAMP/PKA pathway. PACAP has been shown by our laboratory and others to be neuroprotective against ischemia in rodent stroke models. To begin to define the mechanism of this neuroprotection, we employed two cell culture stroke models. Rat cortical neurons subjected to either oxygen-glucose-deprivation or glutamate-induced excitotoxicity underwent cell death as expected. However, treatment with PACAP did not increase neuronal survival in either of the two models, and STC1 over-expression also failed to increase resistance to neuronal cell death during glutamate-induced excitotoxicity. These data suggest that the protective effects of the neurotrophic peptide PACAP and the putative neuroprotectant STC1 during neurodegenerative conditions in vivo are mediated through cells absent in cultures of cortical neurons, such as glial cells. In conclusion, the present study has demonstrated that expression of different PAC1 splice variants determines the degree of activation of two different second messenger pathways that may mediate different functional outcomes during stress-responding. PACAP mediates ERK activation and STC1 induction via non-canonical cAMP signaling. The selective pharmacological activation of this potentially neuroprotective pathway, which is different from the cAMP/PKA pathway critical for learning and memory, could have therapeutic implications for neuroprotection in vivo.

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