The neurotrophic effects of PACAP in PC12 cells: control by multiple transduction pathways

Abstract

Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP) are closely related members of the secretin superfamily of neuropeptides expressed in both the brain and peripheral nervous system, and they exhibit neurotrophic and neurodevelopmental effects in vivo. Like the index member of the Trk receptor ligand family, nerve growth factor (NGF), PACAP promotes the differentiation of PC12 cells, a well-established cell culture model, to investigate neuronal differentiation, survival and function. Stimulation of catecholamine secretion and enhanced neuropeptide biosynthesis are effects exerted by PACAP at the adrenomedullary synapse in vivo and on PC12 cells in vitro through stimulation of the specific PAC1 receptor. Induction of neuritogenesis, growth arrest, and promotion of cell survival are effects of PACAP that occur in developing cerebellar, hippocampal and cortical neurons, as well as in the more tractable PC12 cell model. Study of the mechanisms through which PACAP exerts its various effects on cell growth, morphology, gene expression and survival, i.e. its actions as a neurotrophin, in PC12 cells is the subject of this review. The study of neurotrophic signalling by PACAP in PC12 cells reveals that multiple independent pathways are coordinated in the PACAP response, some activated by classical and some by novel or combinatorial signalling mechanisms.

The Regulator of Calcineurin 1 (RCAN1/DSCR1) Activates the cAMP Response Element-binding Protein (CREB) Pathway

“…Furthermore, the increased basal level of CREB phosphorylation was observed in stable RCAN1-overexpressing cells compared with control cells, thus increasing the physiological relevance of these findings. PACAP38 is an important neuropeptide that was initially isolated from ovine hypothalamus extracts on the basis of its potent ability to activate adenylate cyclase in rat anterior pituitary cells (26,27). Because PACAP38 is one of the external ligands that increase in the concentration of intracellular cAMP, we determined if the phosphorylation of CREB by PACAP38 was enhanced in cells stably overexpressing RCAN1.…”

Characterizations of a synthetic pituitary adenylate cyclase-activating polypeptide analog displaying potent neuroprotective activity and reduced in vivo cardiovascular side effects in a Parkinson's disease model

“…However, the results remained unsatisfactory due in part to the molecular selectivity of the blood-brain barrier (BBB), which prevented the crossing of most drugs investigated for the treatment of this disease, or because they only targeted one aspect of the disease. In this context, the pituitary adenylate cyclase-activating polypeptide (PACAP) is a promising molecule for the development of a therapeutic strategy to cure a neurodegenerative disease such as PD, because it crosses the BBB and exhibits anti-apoptotic, anti-inflammatory and anti-oxidant activities (Nishimoto et al, 2007;Ravni et al, 2006;Reglodi et al, 2004a;Shioda et al, 2006). Indeed, PACAP has been shown to exert neuroprotective effects in experimental models of neurodegeneration, cerebral ischemia and brain injuries (Deguil et al, 2007;Lazarovici et al, 2012;Lee and Seo, 2014;Rat et al, 2011;Reglodi et al, 2011;Tamas et al, 2012).…”

Simultaneous nitric oxide and dehydroascorbic acid imaging by combining diaminofluoresceins and diaminorhodamines

“…Therefore, using the two dyes and appropriate calibrations at two excitation wavelengths and two emission wavelengths, NO and DHA images can be generated, here using both undifferentiated and differentiated pheochromocytoma (PC12) cells. PC12 cells are neural crest-derived cells that can be differentiated to form neuron-like cells (Belliveau et al, 2006;Greene and Tischler, 1976;Ravni et al, 2006). This cellular line contains nNOS, and NO is required for their differentiation (Hindley et al, 1997;Peunova and Enikolopov, 1995;Phung et al, 1999).…”