Our laboratory studies neurotransmitters, neuropeptides, and G protein-coupled receptors, and examines how the resulting downstream signaling pathways regulate neuronal gene expression and function.  Over the last several years, our work has emphasized pituitary adenylate cyclase activating polypeptide (PACAP), a highly conserved and evolutionarily important bioactive peptide which behaves as a neurotransmitter and neurotrophic peptide with a wide spectrum of physiological functions. PACAP shares G protein-coupled receptor subtypes with VIP, a related peptide family member. PACAP binds specifically to PAC1 receptors; both PACAP and VIP bind VPAC1 and VPAC2 receptors with near equal high affinity.  But unlike VPAC receptors which preferentially stimulate adenylyl cyclase, the PAC1 receptor can differentially engage multiple signaling cascades depending on PAC1 receptor isoform expression.  Hence the tissue-specific expression of these PAC1 receptor variants provides a novel molecular means for PACAP to mediate its diverse physiological, neuroprotective and developmental roles.

Currently, our laboratory is following two main lines of enquiry - one relates to the cellular and molecular functions of the PACAP signaling in neuronal systems, and the other to the behavioral roles of PACAP in stress-mediated anxiety-related disorders.  In the former, our cellular and molecular studies employ primary and stably transfected cells to: investigate the impact of PAC1 receptor dimerization on signaling and ligand pharmacokinetics; examine the dynamics and consequences of receptor internalization in endosome signaling platforms; identify the neuronal substrates activated downstream of PAC1 receptor stimulation; and understand the intersection of PAC1 G protein receptor signaling with neurotrophin and Trk pathways.  These studies complement our ongoing studies on the mechanisms that regulate neuronal PACAP expression.

The behavioral studies relate to our observation that stress induces PACAP expression in specific central nervous system stress pathways.  We have shown subsequently that PACAP peptide infusions into specific amygdala-related nuclei facilitate anxiety-like behaviors (anxiogenic) and that the presentation of PAC1 receptor antagonists during stress exposure can attenuate stress-related responses.  These roles for PACAP in stress and anxiety are amplified by our recent observations that serum PACAP levels are elevated in a female population with post-traumatic stress disorder (PTSD) and that these changes are correlated with polymorphism in the estrogen responsive element in the  PAC1 receptor gene.  These observations are novel with potentially important clinical implications.  In addition to work with our collaborators to identify small molecule PAC1 receptor antagonists for translational applications, we are investigating the roles of estrogen in PACAP/PAC1 receptor expression and function, and the cellular mechanisms of PACAP integration into established stress regulators (CRH, serotonin) and pathways (amygdala, dorsal raphe nucleus).  Interestingly, as PACAP is highly expressed in sensory nociceptive systems, we are also initiating studies with our university colleagues to examine how altered PACAP function in pain pathways exacerbates stress-related anxiety behaviors, participates in migraine and may precipitate other related physiological disorders including urinary bladder dysfunction.  These studies in sum will further our understandings of PACAP/PAC1 receptor function and enhance our abilities to target the system for therapeutics in disease.