The cellular mechanisms underlying neurogenesis, neurodevelopment and neuroregeneration are complex processes hat balance neuronal survival and proliferation with differentiation. These processes involve the spatial and temporal orchestration of a succession of neuroregulatory factors and the facility with which particular neurotrophic signals can adapt to diverse signaling pathways appears key to a successful neuronal developmental and regeneration program. Many neuropeptidergic systems are essential components of that process and among neuropeptide families, the vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase activating polypeptides (PACAP) have well establishec roles in neurotransmitter and neurotrophic signaling. In our studies of neuronal transmitter and bioactive peptide production, we identified the high potency and efficacy of PACAP peptides in stimulating superior cervical ganglior SCG) sympathetic neuron transmitter/peptide production and secretion, established the preferential high expressior of only the PACAP-selective PAC1(short)HOP1 receptor splice variant in SCG neurons and demonstrated the unique coupling of PAC1 (short)HOP1 receptor isoform to multiple intracellular signaling cascades. These studies have allowed us to structure studies to define the cellular mechanisms of PACAP/PAC1 receptor function; accordingly, we have hypothesized that the ability for the PAC1 receptor to activate multiple second messenger pathways underlies its functional diversity in regulating the many different facets of PACAP-mediated neurotransmitter and neurotrophic actions. Our work has already suggested novel mechanisms of PAC1 receptor Trp channel activation in PACAP mediated neurotransmissin; we will pursue these and complementary studies with the postulate that PAC1 receptor activation of specific MEK/ERK and P13K/AM trophic signaling pathways during precise developmental periods or altered physiological states, provides critical signals for neuronal proliferation, differentiation or regeneration.
Our aims are: 1) to establish the intracellular signaling mechanisms that transduce the PACAP/PAC1 receptor-mediated neurotrophic signals; 2) define the particular PAC1 receptor-mediated signaling pathway that engages each neurotrophic response; and 3) establish the roles of Tm channels in PACAP function. We feel these studies are unique not only in understanding PACAP/PAC1 receptor actions in physiological context, but also important ir providing essential insights to the diverse roles of G-protein coupled receptor signaling in neuronal function and development. These studies may suggest future strategies to facilitate neuronal regeneration to injury and disease.
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