Pulsatile calcium signalling: Its relevance for cellular information processing

Schöfl, C., Prank K., Brabant G.

Abteilung Klinische Endokrinologie, Medizinische Hochschule Hannover, D-30623 Hannover, Germany

Cells in multicellular organisms communicate via intercellular signals such as hormones in order to ensure controlled function of the whole organism and to allow for adaptive changes in response to environmental stimuli. These intercellular signals can bind to signal-specific receptors on target cells activating distinct intracellular second-messenger systems e.g. the Ca²⁺/phosphoinositide (PI) signalling system, thereby translating the extracellular signal into specific target cell responses such as proliferation, differentiation, or functions. Target cells are in simultaneous contact with many regulatory factors. Many of these factors vary with time in their local concentrations owing to pulsatile release or production. Therefore complex patterns of signalling factors act on each living cell in vivo, stimulating or inhibiting second-messenger pathways with potentially complex dynamics. These intracellular pathways do not operate independently but are extensively interconnected, creating complex networks and patterns of intracellular signals which combine to determine the cell´s response. The potential significance of cross-signalling between second-messenger pathways and of dynamic stimulation of receptors for cellular information processing was investigated using agonist-induced Ca²⁺-signals in hepatocytes as a model. In many excitable as well as non-excitable cells like hepatocytes the cytosolic Ca²⁺ response activated by the Ca²⁺/ PI signalling pathway is pulsatile with repetitive Ca2+-transients. In most cells the frequency of the Ca²⁺-transients is sensitive to changes in hormone concentration suggesting that the Ca²⁺ signal is frequency encoded. In hepatocytes, however, we could demonstrate that the shape, frequency and amplitude of the Ca²⁺-transients is also regulated by agonist-specific cross-signalling or by dynamic receptor stimulation. The potential relevance of changes in the pattern of Ca²⁺ signals for regulation of different cellular Ca²⁺-dependent processes was further investigated in a model of Ca²⁺/calmodulin-dependent kinase activated target proteins. In view of the many intracellular Ca²⁺-dependent effector proteins our results suggest that specific patterns of cytosolic Ca²⁺-signals elicited by cross-signalling or by dynamic receptor stimulation could allow for differential regulation of cellular functions as has been experimentally shown for the differentiation of embryonic neurons [1].
Supported by DFG grant Scho 466/1-3.

[1] Spitzer and Gu (1995) Nature 375: 784

LOCATION	DATE	TIME
Lecture Hall II	Thursday, April 9	09:20 am