Jeffry Lansman

Associate Professor, Teaching Faculty

Email: jeff.lansman / ucsf, edu

513 Parnassus Avenue
Med Sciences Building, Room S1272
San Francisco, CA 94143-0450

Phone: 415-476-1322

Our research is aimed at understanding the mechanisms that control calcium entry into excitable cells. We use electrophysiological and optical methods to study biophysical mechanism controlling calcium channel activity and intracellular calcium accumulation in single cells. Current work is focused on four projects.

Mechanosensitive ion channels in muscle and their role in pathogenic calcium entry in muscular dystrophy. Although a lack of dystrophin has been known for over a decade to be the cause of Duchenne muscular dystrophy, it is still not known how dystrophin deficiency causes muscle cell death. Mice that lack the cytoskeletal protein, dystrophin, have mechanosensitive (MS) channels with abnormally long open times. These channels arise as a result of mechanical perturbations that alter the mechanical properties of the cell membrane. Present research efforts are aimed at determining the molecular identity of the MS channels in muscle, the role of mechanical forces in controlling local calcium ion fluxes in dystrophic muscle using imaging methods, and determing the the role of various cytoskeletal proteins in controlling how tension in the bilayer is coupled to channel gating.

Voltage-gated calcium channel mutations and neurological disease. Mutations in the P/Q-type calcium channel alpha 1A subunit are associated with migraine and cerebellar ataxia in humans. In mice, the leaner mutation occurs at a splice site in the P/Q-type channel alpha 1A subunit gene and produces absence epilepsy and cerebellar ataxia and degeneration. Patch clamp recordings from cerebellar granule cells from leaner mice, show the selective reduction of a specific class of Q-type calcium channel. Reduction in Q-type channels is associated with homeostatic changes in the expression of other types of ion channels responsible for electrical excitability and synaptic transmission. Current experiments are focused on elucidating the compensatory changes in excitability that occur in neurons possessing mutant P/Q-type channels and the mechanisms that contribute to the wide spread cell death during early development of the granule cell population.

Store-coupled calcium entry pathways in neurons. In cultured cerebellar granule cells from mice, activation of group I metabotropic glutamate receptors produces an IP3 and protein kinase C-independent increase facilitation of the L-type current. L-type current facilitation is coupled to the activation of intracellular caffeine- and ryanodine-sensitive calcium stores. We are using whole-cell recordings combined photometric measurements of fura-2 fluorescence and flash photolysis of intracellularly trapped caghed claium-releasing compounds to determine the coupling mechanism between intracellular stores and voltage-gated calcium channels and whether this pathway provides a mechanism for store refilling during repetitive neuronal activity.

Control of gene expression by NMDA receptor channels. Calcium influx through the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor is required for various forms of synaptic plasticity and long lasting changes in neuronal gene expression. In collaboration with the Finkbeiner lab, we are studying how local calcium signals near the the cytoplasmic mouth of NMDA receptor channels are coupled to specific signaling pathways leading to gene expression in the nucleus. Experiments make use of a novel system developed in the Finkbeiner lab in which NMDA receptors (NR1) with mutations in their cytoplasmic domain are transfected into cortical neurons from mice that lack the NR1 subunit. Experiments in this lab are aimed at determining biophysical properties of single NMDA receptors in transfected cells and using the magnitude of calcium-induced inactivation of the whole-cell NMDA currents as an indicator of near-membrane calcium fluxes in mutant channels.