Thomas F. J. Martin, Ph.D. Professor Department of Biochemistry tfmartin@facstaff.wisc.edu

Neural and endocrine cells are key physiological integrators that both receive and emit signals in the form of hormones and neurotransmitters. Our research focuses on the molecular mechanisms that underlie stimulus-secretion coupling, the process by which receptor occupancy and signal transduction events regulate the secretion of hormones and neurotransmitters. Since previous work showed that signal transduction pathways that elevate intracellular Ca²⁺ are responsible for stimulating secretion, current efforts are directed at elucidating the Ca²⁺ -dependent mechanisms that activate secretory granule fusion with the plasma membrane.

Immortalized cell lines of endocrine and neural origin are employed in our studies. PC12 cells of adrenal medullary origin store catecholamines in dense core secretory granules that undergo fusion with the plasma membrane in response to increased Ca²⁺ . Cells permeabilized by a novel method retain a Ca²⁺ -activated secretory response. Studies with the permeable cells have revealed the molecular requirements for Ca²⁺ -activated exocytotic fusion as consisting of ATP and several soluble proteins. ATP acts prior to Ca²⁺ , and distinct soluble proteins are required for the ATP-dependent and Ca²⁺ -activated reactions. Six proteins participate in the ATP-dependent activation step: PEP 1-3, NSF, alpha- and beta-SNAP. The activation step involves lipid phosphorylation and the rearrangement of membrane proteins, termed SNAREs. Fusion is triggered by Ca²⁺ in the ATP-primed cells but requires the soluble protein, CAPS. CAPS is a novel, Ca²⁺ -regulated, neural and endocrine secretory cell-specific protein. Properties of CAPS suggest that it is required for a Ca²⁺ -regulated process involving cytoskeleton-membrane interactions necessary for secretory granule-plasma membrane fusion.

Continuation studies employ biochemical, molecular biological and cell biological strategies to determine the roles of PEP, CAPS, and NSF proteins. This work is directed at uncovering universal mechanisms for neurotransmitter and hormone secretion that underlie processes as diverse as learning and insulin secretion.

Selected Publications: Articles on PubMed

• Lynch KL, Gerona RR, Larsen EC, Marcia RF, Mitchell JC, and Martin TF. (2007). Synaptotagmin C2A Loop 2 Mediates Ca2+-dependent SNARE Interactions Essential for Ca2+-triggered Vesicle Exocytosis. Mol Biol Cell. Epub ahead of print. PMID 17914059
  
  Lynch KL and Martin TF. (2007). Synaptotagmins I and IX function redundantly in regulated exocytosis but not endocytosis in PC12 cells. J Cell Sci. 120:617-627. PMID 17264148
  
  Aikawa Y, Lynch KL, Boswell KL, and Martin TF. (2006). A second SNARE role for exocytic SNAP25 in endosome fusion. Mol Biol Cell. 17:2113-2124. PDF PMID 16481393
  
  
• Aikawa Y, Xia X, and Martin TF. (2006). SNAP25, but not syntaxin 1A, recycles via an ARF6-regulated pathway in neuroendocrine cells. Mol Biol Cell. 17:711-722. PDF PMID 16314394
  
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