SP11 Molecular and integrated responses to the stress signal hydrogen sulphide (H2S)

Project leader: Stefan Heinemann

Background and previous work
Cells endogenously produce the stress mediator hydrogen sulphide (H2S) by the actions of cystathionine gamma-lyase (CSE) in vascular smooth muscle cells and cystathionine beta-synthase (CBS) in the nervous system. H2S is implicated in inflammatory stress conditions and affects physiological systems in a time- and dose-dependent manner, and H2S is a reported modulator of various ion channels. The molecular mechanisms underlying these partially bimodal effects and the crosstalk of H2S signalling with the cellular redox system and other gases such as CO and NO remain to be elucidated.

Specific aims and working programme
The project aims to gain insight how H2S stress affects the function of a selected class of native and recombinant K+ channels and how ROS, CO and NO modulate the H2S-mediated regulation. One of the working hypotheses assumes that graded H2S challenge is protective with regard to subsequent ROS / CO insults. In particular, we will study KCNH2 channels to infer about H2S/ROS/CO/NO modulation of cardiac function and KCNH1 channels to gain insight into the consequences of dysregulating H2S biosynthesis under neuropathological conditions. KCNMA1 channels serve as controls.
Endogenous production of H2S will be altered by using CSE-/- mouse models. To gain deeper insights into the cellular signalling mechanisms involved and their relation to biologically relevant stress situations, cell systems will be studied with/without co-cultivating them with macrophages.
Given the time- and concentration dependence of H2S impact on the proteins investigated, we will devise optical readouts for monitoring the dynamics of cellular H2S and other gaseous messengers to yield a quantitative assessment of adaptive processes on a molecular level.