Research directions
Function of acid-sensing ion channels
Localized changes in pH occur in physiological situations (e.g. neurotransmitter release in synapses) or under pathological conditions (e.g. inflammation, ischemia). We are interested in pH sensing in general, and particularly in one class of pH sensors, the acid-sensing ion channels (ASICs). ASICs are expressed in the central and the peripheral nervous system. There is evidence for roles of ASICs of the central nervous system in memory functions, fear conditioning, pain sensation and cell death during ischemic conditions. ASICs in the peripheral nervous system have been shown to be involved in pain sensation.
The research of my laboratory has two main lines. 1) We investigate how ASICs and other acid-sensitive channels affect the signaling activity of neurons as a function of pH. 2) We analyze in molecular detail the mechanisms by which pH controls opening and closing of the ASIC pore.
To understand the cellular roles of ASICs we measure action potential generation induced by acidification in neurons of the central and peripheral nervous system. By applying different conditions of pH and temperature, and with the use of pharmacological tools, we determine the contribution of different types of pH sensors. To understand on the molecular level how protonation of some key residues of the ASIC extracellular domain leads to opening and desensitization of the channel pore, we try to identify protonation sites and to determine the changes in conformation occurring during channel activity. To this end we combine electrophysiological analysis with site-directed mutagenesis, molecular dynamics simulations and voltage-clamp fluorometry.
