A two-cell biosensor was developed that uses optically detected changes in naturally colored fish chromatophores to measure the neurosecretory output of mammalian neuronal cells. The specific version of the biosensor described here is a continuous flow device that places red-pigmented, dendritic erythrophore cells directly downstream of an immobilized population of PC12 neuronal cells, a well-established model cell-line having neuroendocrine function. Agents known to stimulate catecholamine neurosecretion (secretagogues) were presented to the PC12 cells. It was found that the varying level of neurosecretion from the PC12 cells was measurable by judging the degree of pigment aggregation in the erythrophores. Increases in catecholamine secretion and consequent pigment aggregation were observed for several known secretagogues, including receptor agonists (ATP, acetylcholine), membrane depolarizing agents (high K(+) concentration), and specific neurotoxins (black widow spider venom, alpha-latrotoxin). This particular two-cell biosensor, which is applicable to the detection of any agents that affect the levels of catecholamine secretion from PC12 cells, demonstrates the general principle that the breadth of sensitivity of a biosensor is increased by employing coupled cell types.