Calcium Signalling and Gene Expression

Abstract

A wide variety of compounds acting as extracellular signals cause changes in the free cytosolic Ca²⁺ concentration. These factors include hormones, growth factors, neurotransmitters, but also nutrient and metabolic activators. Ca²⁺ signalling is caused by mobilization of Ca²⁺ from internal stores and by well controlled and timed Ca²⁺ influx from the extracellular space. Ca²⁺ signals address Ca²⁺ dependent enzymes, most importantly Ca²⁺ sensitive protein kinases and phosphatases. The profound influence of Ca²⁺ signalling on gene expression has been recognized a long time ago. As Ca²⁺ signals are short-lived when compared to alterations in differentiated gene expression, it is generally considered that genes coding for short-lived transcription factors (i.e. fos, jun) are the immediate target of Ca²⁺ signalling. Transcription of these immediate early genes (IEG) can be activated without the need for protein synthesis. Ca²⁺ signalling affects differentiated gene expression via changes in the absolute and relative abundance of IEG products, which in turn control the expression of differentiated genes. Ca²⁺ signals can stimulate both transcriptional initiation as well as transcriptional elongation. Initiation of transcription is stimulated by the Ca²⁺ dependent phosphorylation of binding proteins addressing two response elements in the promoter of IEGs: the cAMP response element, CRE, and the serum response element, SRE. Distinct protein kinases are involved in either case. We study the elongation of transcripts of the IEG c-fos beyond the first intron which is favoured by Ca²⁺ signals, involving mechanisms which still are poorly understood. We can show that intron sequences contribute to the control of elongation by Ca²⁺, and that there is a strong interrelation between the transcription control by the promoter and by the intron.