Objective
During the past decade convincing evidence has been accumulated for the neurotransmitter role of ATP both in the periphery and in the CNS. This role is particularly important in smooth muscle excitation and inhibition. Unfortunately, in most studies the effect of ATP on the final step - smooth muscle contraction - has been examined, which did not allow to highlight the underlying intimate mechanisms. As an example, the inhibitory effect of ATP mediated by P2Y receptors in gastrointestinal smooth muscle cells was generally believed to be mediated by SKCa channel activation, though until recently such channels were not observed in the membrane of smooth muscle cells. The data regarding the involvement of intracellular second messengers in the inhibitory action of ATP on gastrointestinal smooth muscle cells is also lacking. Very little is known about the origin of the excitation seen in the presence of apamin in response to ATP or purinergic nerves stimulation. Moreover, under these conditions similar effects are observed in smooth muscle cells during a-adrenoceptors activation by noradrenaline. The present project is the first attempt to approach these problems in all their complexity, and to study the intimate mechanisms of the inhibitory and excitatory effects of ATP on gastrointestinal smooth muscle cells.
Using modern biophysical and pharmacological techniques it is planned to study the main membrane and intracellular events and their underlying mechanisms in a complex process linking P2Y receptor activation to the point of functional response - inhibition or excitation. Extensive research experience of the participants in relevant areas (receptor-operated ion channels, G protein-coupled receptors, intracellular second messengers, Ca 2+ and K+ channels) will ensure that the planned tasks can be accomplished successfully.
Revealing the mechanisms of the major events resulting in contraction/relaxation will contribute towards the design of specific and effective measures to control these steps in a desired manner, either to depress or to potentiate the mechanical response of the tissue to ATP, which may be clinically helpful. Additionally, these new results potentially could have wider biological implications for other excitable and non-excitable cells (astrocytes), where ATP acts as a transmitter, but the application of modern electrophysiological techniques is more difficult or impossible.
Topic(s)
Call for proposal
Data not availableFunding Scheme
Data not availableCoordinator
50931 Köln
Germany