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MOLECULAR CONTROL OF FUSION PORE EXPANSION IN MOUSE ADRENAL CHROMAFFIN CELLS.

Samasilp, Prattana
http://rave.ohiolink.edu/etdc/view?acc_num=case1396426579

Abstract Details

2014, Doctor of Philosophy, Case Western Reserve University, Physiology and Biophysics.
Adrenal chromaffin cells differentially secrete a variety of transmitter molecules into the circulation as a function of sympathetic activation. Activity-dependent release of transmitter species is controlled through regulation of the secretory fusion pore. Under sympathetic tone, basal synaptic activity causes chromaffin cells to selectively secrete modest levels of catecholamine through a restricted fusion pore. In contrast, in response to threat the acute stress reflex elevates sympathetic activation resulting in expansion of the fusion pore to evoke maximal catecholamine release and to facilitate release of co-packaged peptide transmitters. Therefore, fusion pore expansion is a key control point for the activation of the sympatho-adrenal stress response. In this study, I investigate the role of dynamin 1 in the regulation of activity-mediated fusion pore expansion. I show that under elevated stimulation, dynamin 1 is dephosphorylated at Ser-774 by calcineurin. Inhibiting dynamin 1 dephosphorylation restricts fusion pore expansion. I further investigate the downstream signaling cascade of this process. I demonstrate that perturbation of dynamin 1-syndapin binding, an association regulated by calcineurin-dependent dynamin dephosphorylation, and N-WASP function, a syndapin substrate, limits activity-mediated fusion pore expansion. These results demonstrate that the syndapin/N-WASP pathway is involved in the regulation of fusion pore expansion by dynamin 1. Since there are three isoforms of syndapin (syndapins 1- 3) reported in literature, I further explore the expression and localization of syndapin isoforms in mouse adrenal chromaffin cells. I report all syndapin isoforms are expressed in the adrenal medulla. Moreover, I determine the involvement of each syndapin isoform in mediating fusion pore expansion. Mutation of the SH3 dynamin-binding domain of all syndapin isoforms shows that fusion pore expansion and catecholamine release are limited specifically by the mutation of syndapin 3. The mutation also disrupts targeting of syndapin 3 to the cell periphery. In addition, syndapin 3 exists in a persistent colocalized state with dynamin 1, whereas syndapin 1 does not. Together, dynamin 1 dephosphorylation by calcineurin is a key control point of transitioning exocytic modes from kiss and run to full collapse exocytosis. Dephosphorylated dynamin 1 acts through a syndapin 3-N-WASP signaling cascade to regulate the expansion of the fusion pore.
Corey Smith (Advisor)
George Dubyak (Committee Chair)
Stephen Jones (Committee Member)
William Schilling (Committee Member)
David Katz (Committee Member)
Rajesh Ramachandran (Committee Member)
176 p.
Physiology

Recommended Citations

Citations

  • Samasilp, P. (2014). MOLECULAR CONTROL OF FUSION PORE EXPANSION IN MOUSE ADRENAL CHROMAFFIN CELLS. [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1396426579

    APA Style (7th edition)

  • Samasilp, Prattana. MOLECULAR CONTROL OF FUSION PORE EXPANSION IN MOUSE ADRENAL CHROMAFFIN CELLS. 2014. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1396426579.

    MLA Style (8th edition)

  • Samasilp, Prattana. "MOLECULAR CONTROL OF FUSION PORE EXPANSION IN MOUSE ADRENAL CHROMAFFIN CELLS." Doctoral dissertation, Case Western Reserve University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=case1396426579

    Chicago Manual of Style (17th edition)

case1396426579
487
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This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.