Biography

After receiving his B.S. from the University of Notre Dame in 1973, Michael Forte earned his Ph.D. in Genetics from the University of Washington in 1978. He did four years of postdoctoral research in the Laboratory of Molecular Biology at the University of Wisconsin at Madison and became an assistant professor at Case Western Reserve University in 1982. Forte joined the Vollum Institute as scientist in 1986 and was promoted to senior scientist in 1993 with concurrent appointments in the Departments of Cell, Developmental & Cancer Biology and Molecular and Medical Genetics in the School of Medicine. He was also an affiliate member of OHSU’s Jungers Center and the Knight Cancer and Cardiovascular Institutes. Forte was granted the title of Professor Emeritus in 2020.

Summary of research

The Forte lab predominantly utilized genetic approaches in both simple and more complex mammalian systems. Initially, the lab worked on a simple, voltage-gated ion channel in an early attempt to define which regions “move” in response to transmembrane potential changes. These results were used to define the novel conformational transitions that accompany voltage gating of an ion channel.

Their interests then turned to transmembrane signaling in Drosophila. These studies showed that G-protein α subunits are expressed in a spatially and temporally restricted manner during embryogenesis and thus are responsible for mediating important developmental interactions. The lab then focused on the G_sα pathway to demonstrate that elimination of the consensus downstream effector had no effect on pheno­types generated by activation of this pathway. These genetic studies pointed out that Gα pathways in general can mediate their effects by the activation of novel effectors that may be responsible for cell-specific responses in different cell types.

In recent years, the lab focused on the role of mitochondrial Ca²⁺ as regulated through the permeability transition pore (PTP), which regulates the structural re-organization of mitochondria in response to changes in cellular Ca²⁺. The PTP plays a critical role in some of the most widespread and therapeutically challenging human diseases, such as ALS and Alzheimer’s disease. The Forte lab and their collaborators showed that the PTP plays key roles in the disease processes underlying murine models of multiple sclerosis, muscular dystrophies, heart attacks, and stroke. They also successfully identified a number of novel small molecules that serve as potent inhibitors of the PTP. These molecules will be useful in advancing the search for small‑molecule therapeutics for these disorders.

Selected publications

Roy S, Šileikyte. J, Schiavone M, Neuenswander B, Argenton F, Aubé J, Hedrick MP, Chung TD, Forte M*, Bernardi P*, Schoenen FJ*. (2015) Discovery, synthesis, and optimization of diarylisoxazole-3-carboxamides as potent inhibitors of the mitochondrial permeability transition pore. Chem. Med. Chem. 10:1655–1671. (*co-senior authors)

Bernardi P, Rasola A, Forte M, Lippe G. (2015) The mitochondrial permeability transition pore: Channel formation by F-ATP synthase, integration in signal transduction, and role in pathophysiology. Physiol. Rev. 95:1111–1155.

Forte M, Gold BG, Marracci G, Chaudhary P, Basso E, Johnsen D, Yu X, Fowlkes J, Rahder M, Stem K, Bernardi P, Bourdette D. (2007) Cyclophilin D inactivation protects axons in experimental autoimmune encephalomyelitis, an animal model of Multiple Sclerosis. Proc. Nat. Acad. Sci. USA 104:7558–7563.

Wolfgang WJ, Roberts IJ, Quan F, O’Kane C, Forte M. (1996) Activation of protein kinase A-independent pathways by G_sα in Drosophila. Proc. Nat. Acad. Sci. USA 93:14542–14547.

Blachly-Dyson E, Peng SZ, Colombini M, Forte M. (1990) Selectivity changes in site-directed mutants of the VDAC ion channel: Structural implications. Science 247:1233–1236.

Biography

After earning his B.A. degree in Psychology from the University of California at Riverside, Craig Jahr studied Biology at the University of California at Santa Barbara. His Ph.D. in Pharmacology was awarded by the University of California at San Francisco in 1980. Jahr did postdoctoral research at UCSF and Harvard Medical School. He was appointed as an associate research scientist in Molecular Neurobiology at Yale University School of Medicine in 1985 and remained there until his appointment to the Vollum Institute in 1987. Jahr was granted the title of Professor Emeritus in 2017.

Summary of research

Neurons transmit information to each other through specialized connections called synapses. Craig Jahr and his coworkers used electrophysiological and optical techniques to focus on synaptic transmission involving the release of glutamate, a chemical neurotransmitter used at the vast majority of excitatory synapses in the CNS. The excitation is generated by the binding of glutamate to specific receptors embedded in the neuronal membrane. The Jahr lab showed that the duration of excitation determines the period that glutamate remains bound to the receptors rather than the time that is required for sequestration of free glutamate.

Glutamate, like most other neurotransmitters, is released from presynaptic sites following action potential invasion by the fusion of transmitter-filled vesicles to the presynaptic membrane. A widely held belief in neurobiology is that a maximum of a single vesicle can be released per synapse per action potential. Jahr and coworkers have shown that, at certain synapses in the cerebellum and hippocampus, a single action potential can evoke the release of several vesicles per synapse per action potential. This results in a very high concentration of glutamate in the synapse that can saturate the postsynaptic receptors and ensures excitation of the postsynaptic neuron. In addition, it appears that vesicular release can occur not only at the presynaptic active zone, but also from other presynaptic locations that are not associated with postsynaptic specializations. Such ectopic release results in more rapid and complete activation of extrasynaptic receptors and may be necessary to maintain glial membranes close to synapses. Furthermore, non-canonical vesicular release can also occur directly onto two different types of glial cells, activating glial AMPA receptors with similar rates as those on neurons.

Jahr and his colleagues found that glutamate released from the presynaptic terminal is cleared from the cleft very rapidly, within 2 to 3 milliseconds, despite a lack of an extracellular glutamate-degrading enzyme. Ultimately, released glutamate is taken up into neurons and surrounding astrocytes by glutamate transporters. Jahr and coworkers have shown that glutamate transporters bind extracellular glutamate very rapidly and then translocate the neurotransmitter into cells, primarily astrocytes.

More recently, the Jahr lab determined that a form of synaptic plasticity thought to require NMDA receptors in the presynaptic side of the synapse is most likely the result of postsynaptic NMDA receptors, requiring a reexamination of both induction and expression mechanism.
 

Selected publications

Sun W, Hansen KB, Jahr CE. (2017) Allosteric interactions between NMDA receptor subunits shape the developmental shift in channel properties. Neuron 94:58-64.e3.

Carter BC, Jahr CE. (2016) Postsynaptic, not presynaptic NMDA receptors are required for spike-timing-dependent LTD induction. Nature Neurosci. 19:1218-1224.

Christie JM, Chiu DN, Jahr CE. (2011) Ca(2+)-dependent enhancement of release by subthreshold somatic depolarization. Nature Neurosci. 14:62-68.

Matsui K, Jahr CE. (2003) Ectopic release of synaptic vesicles. Neuron 40:1173-1183.

Wadiche JI, Jahr CE. (2001) Multivesicular release at climbing fiber-Purkinje cell synapses. Neuron 32:301-313.

Bergles DE, Roberts JD, Somogyi P, Jahr CE. (2000) Glutamatergic synapses on oligodendrocyte precursor cells in the hippocampus. Nature 405:187-191.

Otis TS, Kavanaugh MP, Jahr CE. (1997) Postsynaptic glutamate transport at the climbing fiber-Purkinje cell synapse. Science 277:1515-1518.

Jahr CE. (1992) High probability opening of NMDA receptor channels by L-glutamate. Science 255:470-472.

Lester RA, Clements JD, Westbrook GL, Jahr CE. (1990) Channel kinetics determine the time course of NMDA receptor-mediated synaptic currents. Nature 346:565-567.

Biography

John Adelman received his Ph.D. in Microbiology and Immunology from OHSU in 1988. He holds a B.A. and an M.S. in Microbiology from the University of Connecticut. After a year as a research assistant at Yale University, he spent five years as a research associate at Genentech with Peter Seeburg. He arrived at the Vollum Institute in 1985, where he did his graduate research with Ed Herbert, the founding director of the Vollum Institute. After receiving his Ph.D., he accepted a faculty position at the Vollum and was promoted to senior scientist in 1998. Adelman was granted the title of Professor Emeritus in 2017.

Summary of research

The Adelman laboratory concentrated on the molecular physiology of potassium channels with a major focus on small-conductance calcium-activated potassium channels (SK channels) that are gated solely by intracellular Ca²⁺ ions. Our laboratory cloned the SK channel family and determined that Ca²⁺ gating is mediated by co-assembled calmodulin, opening the field of ‘calmodulation’ of ion channels. We further showed that in hippocampal CA1 pyramidal neurons the SK channels are expressed in dendritic spines, dictated by interaction with a novel synaptic scaffold protein, where they are co-assembled with NMDA receptors into a signaling microdomain within the postsynaptic density. Thus, synaptically evoked Ca²⁺ influx through NMDAr channels activates neighboring SK channels, which shape EPSPs; SK channel activity reduces the magnitude of AMPAr mediated depolarization thereby dynamically limiting the degree of voltage-dependent Mg²⁺ unblock of NMDAr and NMDAr-dependent Ca²⁺ influx that is important for synaptic plasticity. This modulatory role of SK channels on EPSPs is abolished following the induction of LTP due to internalization of the SK channel proteins due to direct phosphorylation by protein kinase A. Therefore, SK channel plasticity contributes together with increased AMPAr function to the increased EPSP that underlies LTP. These cellular roles are reflected by behavioral studies that showed that blocking SK channels in mice facilitated, while transgenic over-expression severely impaired the acquisition of hippocampal-dependent tasks.

Selected publications

Kim G, Luján R, Schwenk J, Kelley MH, Aguado C, Watanabe M, Fakler B, Maylie J, Adelman JP. (2016) Membrane palmitoylated protein 2 is a synaptic scaffold protein required for synaptic SK2-containing channel function. eLife 5:e12637.

Allen D, Bond CT, Luján R, Ballesteros-Merino C, Lin MT, Wang K, Klett N, Watanabe M, Shigemoto R, Stackman RW Jr, Maylie J, Adelman JP. (2011) The SK2-long isoform directs synaptic localization and function of SK2-containing channels. Nature Neurosci. 14:744-749.

Ngo-Anh JT, Bloodgood BL, Lin M, Sabatini BL, Maylie J, Adelman JP. (2005) SK channels and NMDA receptors form a Ca²⁺-mediated feedback loop in dendritic spines. Nature Neurosci. 8:642-649.

Bond CT, Sprengel R, Bissonnette JM, Kaufmann WA, Pribnow D, Neelands T, Storck T, Baetscher M, Jerecic J, Maylie J, Knauss H-G, Seeburg PH, Adelman JP. (2000) Respiration and parturition affected by conditional overexpression of the small conductance Ca²⁺-activated K⁺ channel subunit, SK3. Science 289:1942-1946.

Xia X-M, Fakler B, Wayman G, Rivard A, Johnson-Pais T, Keen JE, Ishii T, Hirschberg B, Bond CT, Lutsenko S, Maylie J, Adelman JP. (1998) Mechanism of calcium-gating in small conductance calcium-activated potassium channels. Nature 395:503-507.

Köhler M, Hirschberg B, Bond CT, Kinzie JM, Marrion NV, Maylie J, Adelman JP. (1996) Small conductance, calcium-activated potassium channels from mammalian brain. Science 273:1709-1714.

Biography

After undergraduate studies at the Freie Universtät in Berlin, Wolfhard Almers attended graduate school at Duke University and the University of Rochester, where he received his Ph.D. in Physiology in 1971. He then spent three years as a postdoctoral fellow at the Physiological Laboratory at Cambridge University. He joined the Department of Physiology and Biophysics at the University of Washington as an assistant professor in 1974 and rose to professor in 1984. In 1992, he became the director of the Department of Molecular and Cellular Research, Max-Planck Institute, and from 1995 to 1999 was a professor in the Faculty of Biology, University of Heidelberg. In 1999, he joined the Vollum Institute as a senior scientist. In April of 2006, he was elected to the National Academy of Sciences. Almers was granted the title of Professor Emeritus in 2016.

Summary of research

Eukaryotic cells pack enzymes, hormones, and transmitters into secretory vesicles and release them when the vesicles fuse with the plasma membrane during exocytosis. Cells must next retrieve the vesicle membrane by endocytosis to keep the plasma membrane from getting too large or contaminated. In the Almers lab, exo- and endocytosis are studied in live neurons and endocrine cells at the level of single vesicles and single molecules. Capacitance measurements are used to track the cell surface with millisecond time resolution as it changes during exo- and endocytosis. Even at their best, however, such electrophysiological recordings can only report how many vesicles undergo exo- and endocytosis and when these events occur. To detect signals from vesicles even before exocytosis and from the remnants of vesicles afterwards, the lab uses total internal reflection fluorescence microscopy, a method that lets them selectively image the surfaces of living cells to a depth of 100 nanometers. Vesicles can be imaged as they dock at the plasma membrane and then undergo exocytosis or as they withdraw from the plasma membrane during endocytosis. By labeling individual proteins with different colors, the group can observe the time-resolved recruitment and release of proteins during single exocytic and endocytic events. Questions of interest include: How do cells determine where on their surface vesicles dock for exocytosis? Once docked, in what sequence do vesicles recruit the proteins required for exocytosis? What are the mechanisms of membrane fusion and fission? How do cells select membrane for endocytosis? How is endocytosis regulated? Although the primary focus is on secretion and synaptic transmission, these questions relate broadly also to how cells crawl and determine their shape.

Selected publications

Barg S, Knowles MK, Chen X, Midorikawa M, Almers W. (2010) Syntaxin clusters assemble reversibly at sites of secretory granules in live cells. Proc. Natl. Acad. Sci. USA 107:20804-20809.

Knowles MK, Barg S, Wan L, Midorikawa M, Chen X, Almers W. (2010) Single secretory granules of live cells recruit syntaxin-1 and synaptosomal associated protein 25 (SNAP-25) in large copy numbers. Proc. Natl. Acad. Sci. USA 107:20810-20815.

An SJ, Almers W. (2004) Tracking SNARE complex formation in live endocrine cells. Science 306:1042-1046.

Merrifield CJ, Feldman ME, Wan L, Almers W. (2002) Imaging actin and dynamin recruitment during invagination of single clathrin-coated pits. Nature Cell Biol. 4:691-698.

Zenisek D, Steyer JA, Almers W. (2000) Transport, capture and exocytosis of single synaptic vesicles at active zones. Nature 406:849-854.

Biography

After receiving his B.S. in Chemistry from the University of Idaho in 1966, Soderling pursued his Ph.D. in Biochemistry at the University of Washington and graduated in 1970. He spent 17 years at Vanderbilt Medical School as a professor of Molecular Physiology and Biophysics and as Investigator of the Howard Hughes Medical Institute from 1976 to 1989. In 1991, Soderling joined the Vollum Institute as a senior scientist with concurrent appointments as professor in the Departments of Biochemistry and Molecular Biology and Cell and Developmental Biology in the School of Medicine. At OHSU he initiated and directed (1992-1997) the Ph.D. program in neurosciences and served as associate director of the Vollum Institute (1991-2001). Soderling was granted the title of Professor Emeritus in 2012.

Summary of research

Intracellular calcium (Ca²⁺) is a major regulator of cellular functions, particularly in brain cells. As the Ca2+ concentration inside the cell rises, Ca²⁺ interacts with calmodulin (CaM), and this complex interacts with, and alters the functions of a large number of proteins inside cells. The Soderling lab focused on protein kinases (CaMKs) activated by binding Ca²⁺/CaM. These CaMKs modulate a variety of cellular functions by adding phosphate groups to proteins including ion channels, transcription factors, cytoskeletal proteins, and proteins (enzymes) that control the chemistry of the cell. CaMKII phosphorylates glutamate receptor ion channels (AMPA receptors) and translation factors (CPEB) to regulate synaptic current in learning and memory paradigms such as long-term potentiation (LTP). Recent studies identified multiple roles for CaMKI in neuronal development and plasticity including regulation of axonal growth cone morphology, dendritic branching and maturation of spines and synapses. Thus, these CaMKs participate in distinct steps of the complex processes of neuronal development and learning/memory in the brain.

Selected publications

Fortin DA, Srivastava T, Dwarakanath D, Pierre P, Nygaard S, Derkach VA, Soderling TR. (2012) Brain-derived neurotrophic factor activation of CaM-kinase kinase via transient receptor potential canonical channels induces the translation and synaptic incorporation of GluA1-containing calcium-permeable AMPA receptors. J. Neurosci. 32:8127-8137.

Srivastava T, Fortin DA, Nygaard S, Kaech S, Sonenberg N, Edelman AM, Soderling TR. (2012) Regulation of neuronal mRNA translation by CaM-kinase I phosphorylation of eIF4GII. J. Neurosci. 32:5620-5630.

Fortin DA, Davare MA, Srivastava T, Brady JD, Nygaard S, Derkach VA, Soderling TR. (2010) Long-term potentiation-dependent spine enlargement requires synaptic Ca²⁺-permeable AMPA receptors recruited by CaM-kinase I. J. Neurosci. 30:11565-11575.

Saneyoshi T, Wayman GA, Fortin D, Davare M, Hoshi N, Nozaki N, Natsume T, Soderling TR. (2008) Activity-dependent synaptogenesis: regulation by a CaM-Kinase Kinase/CaM-Kinase I/betaPIX signaling complex. Neuron 57:94-107. (see commentary in Neuron 57:3-4)

Wayman GA, Impey S, Marks D, Saneyoshi T, Grant WF, Derkach V, Soderling TR. (2006) Activity-dependent dendritic arborization mediated by CaM-kinase I activation and enhanced CREB-dependent transcription of Wnt-2. Neuron 50:897-909. (see commentaries in Neuron 50:813-5; Science STKE 2006(342):tw220; and Nature Rev. Neurosci. 7:598.)