Steven S. Carlson
Dept.: Professor, Department of Physiology & Biophysics
Neuroscience Focus Group: Cell and Molecular Neuroscience, Excitable Membranes and Synaptic Transmission
Our lab is interested in the molecular recognition events between pre- and postsynaptic cells during synaptogenesis. This recognition allows the nervous system to wire itself correctly during development. We wish to know how the presynaptic axon initially identifies the correct target cell, then how the sites of exocytosis, the active zones, of the nerve terminal become correctly aligned with the neurotransmitter receptors on the postsynaptic cell. To understand these events we must identify the proteins that mediate them, the receptors of the presynaptic plasma membrane and their postsynaptic ligands. At the neuromuscular synapse a synaptic isoform of laminin is present in the synaptic cleft secreted by the muscle cell. Laminin is a large trimeric protein of 700-900 kD containing alpha, beta , and gamma chains. It is known that mice which lack the laminin beta 2 chain have few active zones and the synaptic vesicles are not clustered at the presynaptic membrane. What presynaptic receptor mediates this effect? We have found that the laminin beta 2 chain binds the alpha subunit of the presynaptic voltage-gated calcium channel (VGCC). This is the same channel that opens in response to membrane depolarization allowing Ca+2 to enter the nerve terminal and trigger neurotransmitter release. Blocking the interaction between the beta 2 chain and VGCC during the first week of postnatal development causes the active zones to disassemble. Why is this interaction critical to active zone assembly? We hypothesize that the binding of laminin to the VGCC in the presynaptic membrane prevents the channel from being endocytosed and recycled, so it can be used as an anchor for building the active zone. In support this idea, we find that the VGGC which is bound to laminin is also complexed with the cytosolic active zone protein piccolo. We are in the process of testing our anchorage hypothesis of active zone formation.