The transfer of information by chemical signals during complex biological processes can, with increasing frequency, be described in terms of interacting signal pairs. External signalling is rarely monolithic; rather, signal pairs are utilized in processes such as hormone secretion, neurotransmission, cell growth and differentiation. The dualism of external signalling often results in the occurrence of synergy. One signal appears to turn the cell on or off, and its synergistic partner increases cell responsiveness, providing gain control of the cellular response. ACTH release provoked by certain stressors arises from a synergistic interaction between two hypothalamic hormones: corticotropin releasing hormone (CRH) and a modulator such as vasopressin (AVP). The pituitary ACTH cell has been used to unravel the intracellular messenger equivalents of an external signal interaction that generates synergy. Research emphasizes the single cell approach. Direct measurements of intracellular free Ca2+ were performed using the Ca2+-sensitive fluorescent probe fura-2/AM and instrumentation for digital image processing. A reverse haemolytic plaque assay was used to measure cumulative ACTH release from single pituitary cells in culture. What is the physiological role of intracellular Ca2+ as a messenger? What are the feedforward and feedback relationships between major second messengers [cyclic AMP, diacylglycerol (DAG), inositol 1,4,5-trisphosphate (Ins(1,4,5)P3)] and intracellular Ca2+? That is, how are individual messenger circuits “wired' within ACTH cells. Intracellular Ca2+ may act as a common signal into which interacting second messenger signals [cyclic AMP, Ins(1,4,5)P3, DAG] are transduced and integrated to govern ACTH release. A novel circuit of messenger pathways linked by Ca2+ is proposed as the intracellular basis for the synergistic interaction of CRH- and AVP-regulated ACTH release.

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