John Adelman, Ph.D.
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. After receiving his Ph.D., he accepted a faculty position at the Vollum and was promoted to senior scientist in 1998. Adelman holds a concurrent appointment in the Department of Cell and Developmental Biology.
Summary of Current Research
Small-conductance calcium-activated potassium channels (SK channels) are gated solely by intracellular Ca2+ ions and are fundamental regulators of neuronal excitability. Our laboratory cloned the SK channel family and currently focuses on two main areas.
First, we are investigating the physiological roles of SK channels in hippocampus. Here, SK channel activity affects synaptic plasticity and in behavioral experiments SK channel activity alters hippocampal memory encoding. In brain slices, blocking SK channels with the SK-specific toxin, apamin, facilitates the induction of synaptic plasticity while transgenic over-expression of SK2 channels impairs the induction of synaptic plasticity. We have determined the likely cellular basis for these effects. We have found that in hippocampal CA1 neurons, SK channels are expressed predominantly throughout the dendrites and in spines, where they are co-assembled with NMDA receptors into a signaling microdomain within the postsynaptic density. In CA1 dendritic spines, 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 likely 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 in which we have demonstrated that blocking SK channels in mice by systemic apamin administration facilitated, while transgenic over-expression of SK2 severely impaired, the acquisition of hippocampal-dependent tasks. Current efforts are directed to examining the consequences of SK channel plasticity, the longer-term regulation of SK expression in spines, their roles in LTD, and the molecular and cellular mechanisms that engender their plasticity.
Second, the laboratory is testing the hypothesis that a given subtype of SK channel can serve multiple roles in the same neuron by differential subcellular localization and interactions with distinct sets of microdomain partner proteins, forming an array of Ca2+ signaling complexes. This is being approached by a combination of proteomics, cell biology, and electrophysiology, using wild type and transgenic mice. In this project, additional regulatory proteins have been discovered including protein kinase CK2 and protein phosphatase 2a (PP2a), that are stably associated components to the SK channel complex. In this complex, CK2 phosphorylates and PP2a dephosphorylates CaM modulating the effective Ca2+-sensitivity of the channels. A novel mechanism for integrating metabolic signals may operate through CK2, and this is being investigated using biochemical, electrophysiological, and crystallographic approaches. In addition, we are reintroducing mutant SK channels that either cannot be regulated by CK2 or cannot be regulated by PP2a into the hippocampus of null mice to determine the consequences for synaptic plasticity and learning and memory. Proteomics has also identified associated proteins that are likely involved in the mechanisms underlying SK channel plasticity and these are also being investigated.
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. Nat. Neurosci. 14:744-749.
Lin MT, Luján R, Watanabe M, Frerking M, Maylie J, Adelman JP. (2010) Coupled activity-dependent trafficking of synaptic SK2 channels and AMPA receptors. J. Neurosci. 30:11726-11734.
Lin MT, Luján R, Watanabe M, Adelman JP, and Maylie J. (2008) SK channel plasticity contributes to LTP at Shaffer collateral synapses. Nature Neurosci. 11:170-177.
Cueni L, Canepari M, Luján R, Emmenegger Y, Watanabe M, Bond CT, Franken P, Adelman JP, and Lüthi A. (2008) T-type Ca2+ channels, SK2 channels and SERCAs gate sleep-related oscillations in thalamic dendrites. Nature Neurosci. 11:683-692.
Hammond RS, Bond CT, Strassmaier T, Ngo-Anh TJ, Adelman JP, Maylie J, and Stackman RW. (2006) Small-conductance Ca2+-activated K+ channel type 2 (SK2) modulates hippocampal learning, memory, and synaptic plasticity. J. Neurosci. 26:1844-1853.
Ngo-Anh JT, Bloodgood BL, Lin M, Sabatini BL, Maylie J, and Adelman JP. (2005) SK channels and NMDA receptors form a Ca2+-mediated feedback loop in dendritic spines. Nature Neurosci. 8:642-649.
Stackman RW, Hammond RS, Linardatos E, Gerlach AC, Maylie J, Adelman JP, and Tzounopoulos T. (2002) Small conductance Ca2+-activated K+ channels modulate synaptic plasticity and memory encoding. J. Neurosci. 22:10163-10171.
Schumacher MA, Rivard AF, Bachinger HP, and Adelman JP. (2001) Structure of the gating domain of a Ca2+-activated K+ channel complexed with Ca2+/calmodulin. Nature 410:1120-1124.
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, and 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, and 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, and Adelman JP. (1996) Small conductance, calcium-activated potassium channels from mammalian brain. Science 273:1709-1714.