KAREN M. BRAAS

Research Associate Professor
Anatomy and Neurobiology

Ph.D., Northwestern University, 1983
Postdoctoral training, Johns Hopkins University

Karen.Braas@uvm.edu

Biologically active peptides are critical modulators of many neuroendocrine functions, having essential roles as hormones, neurotransmitters, and growth factors. Our studies integrate biochemical, cell biological, electrophysiological, morphological and molecular biological methodologies to analyze the regulation of neuropeptide expression in autonomic neurons under normal and altered physiological conditions. Pituitary adenylate cyclase-activating polypeptides (PACAP) are abundantly expressed and have diverse functions in the nervous and endocrine systems. In the nervous system, PACAP peptides not only have essential roles in basic neuronal communication and signaling, but they also have neurotrophic properties that promote neuronal survival, mitosis, proliferation and differentiation.

The mechanisms underlying the regulation of neuronal PACAP expression appear to differ considerably from those that regulate other neuropeptides. We have found that neuronal PACAP is upregulated dramatically only under paradigms that simulate increased neuronal activity or injury and repair. Depolarization of rat sympathetic neurons, an established model of activity-dependent modulation of neurons, stimulates cellular PACAP content and release. Axotomy of superior cervical ganglion (SCG) principal neurons, a model of neuronal injury that differentially induces peptide plasticity, augments PACAP gene expression which may be related to the regeneration responses to injury.

The mechanisms underlying these striking increases hinge on the expression of multiple proPACAP transcripts. We are currently characterizing the rat proPACAP gene organization and mRNA variants; the PACAP transcripts we have identified appear to be generated by alternative 3' endonucleolytic cleavage and polyadenylation, and alternative 5' noncoding region exon splicing. Sequence elements in the 3' and 5' untranslated regions of mature transcripts are critical for mRNA stability and translatablilty. Although mRNA have identical PACAP precursor protein coding regions, studies have begun to demonstrate that differences in the structures of the noncoding regions of alternative proPACAP transcript variants have significant impact on mRNA stability and translational efficiency, and, ultimately, on the amount of bioactive PACAP synthesized. The functional significance of the increased neuronal PACAP expression observed in the injury response, including modulation of gene expression, neuron survival, and neuritogenesis, is also under examination.

In collaboration with other investigators, additional studies are examining PACAP modulation of sympathetic, parasympathetic, and olfactory epithelial neuron functions through activation of intracellular signaling pathways through specific isoforms of the PACAP-selective PAC1 receptor.

White, S. L., V. May, K. M. Braas (2000). Organization of the rat PACAP gene. Ann. N. Y. Acad. Sci. 921:370-372.

Beaudet, M. M., R. L. Parsons, K. M. Braas, V. May (2000). Mechanisms mediating pituitary adenylate cyclase-activating polypeptide depolarization of rat sympathetic neurons. J. Neurosci. 20:7353-7361.

Braas, K. M. and V. May (1999). Pituitary adenylate cyclase-activating polypeptides directly stimulate sympathetic neuron neuropeptide Y release through PAC1 receptor isoform activation of specific intracellular signaling pathways. J. Biol. Chem. 274:27702-27710.

Harakall, S. A., C. A. Brandenburg, G. A. Gilmartin, V. May and K. M. Braas (1998). Induction of multiple pituitary adenylate cyclase activating polypeptide (PACAP) transcripts through alternative cleavage and polyadenylation of proPACAP precursor mRNA. Ann. N. Y. Acad. Sci. 865:367-374.

Braas, K. M., V. May, S. A. Harakall, J. C. Hardwick, and R. L. Parsons (1998). Pituitary adenylate cyclase activating polypeptide expression and modulation of neuronal excitability in guinea pig cardiac ganglia. J. Neurosci. 18:9766-9779.

Brandenburg, C. A., V. May, and K. M. Braas (1997). Identification of endogenous sympathetic neuron pituitary adenylate cyclase-activating polypeptide (PACAP): depolarization regulates production and secretion through induction of multiple propeptide transcripts. J. Neurosci. 17:4045-4055.