Stephan Kellenberger, MER, PD
Stephan Kellenberger received his PhD in 1994 from the University of Bern for research on GABAA receptor function performed with Erwin Sigel. After his post-doctoral training with W.A. Catterall at the University of Washington, Seattle, he joined the Department of Pharmacology of the UNIL in 1997. He has been leading his own research team since 2001.
Keywords: ion channel, patch-clamp, pH dependence, neuron, channel gating, structure function relationship
Although protons are present in exceedingly low concentrations in most extracellular fluids, they nevertheless have a major impact on the function of most proteins. Localized changes in pH occur under physiological (e.g. neurotransmitter release in synapses) or pathological (e.g. inflammation, ischemia) situations. We study the function of acid-sensing ion channels (ASICs) a novel family of ion channels that are activated by protons. ASICs are expressed in the central nervous system and in sensory neurons. ASICs respond with a rapidly activating and subsequently desensitizing (inactivating) current to extracellular acidification. There is evidence for roles of ASICs of the central nervous system in memory functions, fear conditioning and cell death during ischemic conditions. ASICs in the peripheral nervous system have been shown to be involved in pain sensation.
Our laboratory investigates ASIC function on the cellular and molecular level. On the cellular level we are investigating the consequences of ASIC activity on neuronal signaling. In nociceptive sensory neurons we are investigating the contribution of ASICs as pH sensors in pain sensation. On the molecular level we use different approaches to address the questions of how ASIC opening and closing is controlled and how ASIC function is regulated. In a recent study we have identified putative proton-sensing residues in ASIC1a, showing that protonation occurs at several sites within a channel subunit. We also provide evidence for conformational changes induced by extracellular acidification (see Fig. 2).
The figure shows on the left schematically the presence of ASICs and voltage-gated Na (Nav) and K (Kv) channels in a neuron. The activation of ASICs by lowering of the extracellular pH induces a depolarization as shown in the experimental trace on the right, activating the voltage-gated channels and thereby leading to a burst of action potentials.
Figure 2A shows on the ASIC1a structural model, in one of the three subunits, the residues that are likely proton sensors, based on a computational and functional approach (Liechti et al., JBC 285, pp 16315). B, Illustration of predicted conformational changes induced by acidification. The contours of the channel are indicated in grey and the vertical central axis is indicated by a black line. One subunit with its five subdomains is shown in color (red: transmembrane segments, yellow: palm, orange: β-ball, blue: thumb, purple: finger, turquoise: knuckle) and the contours of a second subunit are indicated by an interrupted grey line. During ASIC activation, the thumb moves towards the β-ball (indicated by red arrows), leading to opening and subsequent inactivation. Inactivation involves a movement of the palm domains towards the central vertical axis, as indicated by the blue arrows.