Mammalian neurosecretory neurons are excellent models for understandingthe relationship between spike discharge patterns and hormone/transmitter release in the central nervous system. Neurosecretory neurons adopt a bursting pattern that promotes maximally efficient stimulus-secretion coupling at the nerve terminal. The phasic bursting activity in vasopressin neurons is exemplary of this pattern, and relatively unique in ihat it can be studied in vitro, as it results largely from intrinsic membrane properties. The global hypothesis of this proposal is that phasic burstingper se can be explained largely by the understanding of one primary current, its modulation by Ca++, and its autoregulation by dynorphin through Kopiate receptors.
The Specific Aims are:
Aim 1) Determine the ion species, underlyingconductance change, and Ca++-dependence of the current underlying the DAP (IDAP)- Experimentally, we will test several predictions from a powerful computational model simulating phasic activity developed during the past grant period. We predict that the plateau potential underlying bursts results from a Ca++ dependent inhibition of a K+ leak current, such that this current attains voltage-dependence in elevated [Ca++]..
Aim 2) Determine the mechanism of the autoregulatory inhibition of VP neurons via Kopiate receptors. We predict that dynorphin, released locally during a burst from vasopressin neurons, shifts the Ca++ sensitivity of a K+ leak current rightward, raising its threshold, and terminating the burst.
Aim 3) Determine the role of autoregulation in the variability of phasic bursting expression in vitro. We predict that phasic bursting is correlated with the ability of dynorphin to regulate the DAP and burst length and complimentarily, that deficits in phasic bursting activity are due to deficits in autoregulation. A corollary is that phasic bursting may be related to the degree of dendritic arbor present. Understanding the origin of phasic bursting is critical to understanding how VP release is controlled in both physiological and pathophysiological conditions. VP release is critical to normal water balance and cardiovascular regulation. PERFORMANCE. SITE(S) (organization, city, state) University of Tennessee Health Science Center Department of Anatomy and Neurobiology 855 Monroe Avenue Memphis, TN 38163 KEY PERSONNEL. See instructions. Use continuation pages as neededto provide the required information in the format shown below. Start with Principal Investigator. List all other key personnel in alphabetical order, last name first. Name Organization Role on Project William E. Armstrong, Ph.D. Universityof Tennessee, Memphis Principal Investigator Ryoichi Teruyama, Ph.D. University of Tennessee, Memphis Co-Investigator Jay Callaway, Ph.D. University of Tennessee, Memphis Co-Investigator Angela Cantrell, Ph.D. Universityof Tennessee, Memphis Co-Investigator Chunyun Li Universityof Tennessee, Memphis Postdoc To be named Universityof Tennessee, Memphis Research Technician Peter Roper, Ph.D. NIH, NIDDK Collaborator/consultant Disclosure Permission Statement. Applicable to SBIR/STTR Only. Seeinstructions. L~] Yes TTNO PHS 398 (Rev. 05/01) Page 2 Number pages consecutively at the bottom throughout Form Page 2 the application. Do not use suffixes such as 2a, 2b. Principal Investigator/Program Director (Last, First, Middle): The name of the principal investigator/program director must be provided at the top of each printed page and each continuation page. RESEARCH GRANT TABLE OF CONTENTS Page Numbers Face Page 1 Description,
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