John Adelman

Ph.D. in Microbiology - OHSU, 1988
Senior Scientist - Vollum Institute
Joint Professor - Department of Cell and Developmental Biology
Joint Professor - Molecular and Medical Genetics

The Adelman laboratory studies the structure, function, and physiological roles of small conductance calcium-activated potassium channels (SK channels). These channels perform fundamentally important functions for excitable cells in the CNS and peripheral tissues. They are activated by elevated levels of intracellular calcium such as occur following an action potential. Their hyperpolarizing influence modulates the time between action potential spikes within a burst, and gives rise to spike-frequency adaptation where their accumulated activity results in a hyperpolaraization that is deep and long lasting, prohibiting a subsequent action potential. Together, regulation of interspike interval and spike-frequency adaptation shape the basic patterns of neuronal communication.

We employ a diverse technical repertoire to understand SK channels, using a wide range of molecular biological, biochemical, and electrophysiologcial techniques. We have a close interactive relationship with laboratory of Dr. Maylie, that has provided a very productive synergy.

The SK channel family was cloned by our laboratory, and heterologous expression studies detailed their biophysical and pharmacological profiles (Kohler et al, Science, 1996). Subsequently we discovered that calcium ions gate SK channels by binding to a constitutively bound calcium senosor, calmodulin (CaM). Calcium binding to CaM motivates conformational changes in the channel subunits and opeing of the ion-conducting pore (Xia et al, Nature, 1998). Using reagents developed in our laboratory, this novel mechanism has been shown to be widespread for many calcium-sensitive ion channels. Recently, we solved the crystal structure of the CaM binding domain of the SK channels complexed to CaM, revealing their atomic details, which have predicted remarkable and unexpected models for how the gating aparatus functions (Schumacher et al, Nature, 2001). These predictions are currently being tested.

To understand the physiological roles of each of the three member sof the SK channel family, we developed a powerful new approach to transgenic mice, and have used homologous recombination to engineer mice in which each of the SK channel genes may be accutely regulated (swithched on or off) in vivo, while retaining precise tissue-specific and developmenal-specific expression. We are currently using these animals to study paradigms of neuronal function and learning and memory pathways, as well as a host of peripheral tissue physiology. We have recently uncovered roles for one of the SK channels in regulation of respiratory functions and in parturition (Bond et al, Science, 2000).

To investigate the subcellular neighborhoods in which SK channels exist, we have used the 2-hybrid genetic screen to identify a number of proteins that physically interact with SK channels. Some of these proteins interact with all three members of the SK channel family, while others show selectivity. Currently, we have developed a multidisciplinary approach to understanding the significance of these protein-protein interactions.

Selected references:

Pedarzani P, Mosbacher J, Rivard A, Cingolani LA, Oliver D, Stocker M, Adelman JP, Fakler B (2001) Control of electrical activity in central neurons by modulating the gating of small conductance Ca2+-activated K+ channels. J. Biol. Chem. 276:9762-9769.

Schumacher MA, Rivard AF, Adelman JP (2001) Structure of the Gating Domain from Small-conductance Ca2+-activated K+ Channels 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, Adelman JP (2000) Respiration and Parturition Affected by Conditional Overexpression of the Small Conductance Ca2+-activated K+ Channel Subunit, SK3. Science 289:1942-1946.

Keen JE, Khawaled R, Farrens DL, Nelands T, Rivard A, Bond, CT, Fakler B, Adelman JP, Maylie J (1999) Domains responsible for constitutive and Ca2+-dependent interactions between calmodulin and small conductance Ca2+-activated potassium channels. Journal of Neuroscience 19:8830-8838.

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

Ishii TM, Silvia C, Hirschberg B, Bond CT, Adelman JP, Maylie J (1997) A human intermediate conductance calcium-activated potassium channel. Proc.Natl. Acad. Sci. USA 94:11651-11656.

Ishii TM, Maylie J, Adelman JP (1997) Determinants of apamin and curarine block in SK potassium channels. J. Biol. Chem. 272:23195-23200.

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

To contact Dr. Adelman directly: adelman@ohsu.edu