As a professor at the University of California, Berkeley, Tsien led a lab that developed the calcium probes fura-2 and indo-1 ( 4, 5), which are elaborations of the BAPTA architecture. BAPTA binds calcium through four carboxylate groups ( Fig. 1). The first Ca 2+ chelator Tsien developed, 2-bis( o-aminophenoxy)ethane- N, N, N′, N′-tetraacetic acid, or BAPTA ( 3), remains widely used because of its rapid binding kinetics, high selectivity for calcium, and insensitivity to pH changes in the physiological range. Tsien considered electrophysiology as an undergraduate, but by the time he started his graduate research at Cambridge, he was focused on chemical approaches. “Calcium was central to everything-but it was very difficult to measure,” Kao said. The ion was already known as an important signal carrier central to muscle contraction, synaptic transmission, and many other physiological functions ( 2). Tsien began to pursue an interest in calcium signaling early in his scientific career. In one JBC Classic article on such probes, “Ca 2+ indicators based on fluoresceins and rhodamines,” Akwasi Minta, Kao, and Tsien introduced several fluorescent indicators of Ca 2+ concentration that could be used in cells ( 1). Many modern indicators derive from a series of probes that Tsien’s lab developed. Today, researchers can use a variety of fluorescent indicators to visualize the activity of calcium and other second messengers in living cells. In the 1970s, Kao said, measuring calcium was “a very rarefied, arcane art” that depended on a deep knowledge of electrophysiology. Before launching that project in the 1990s, Tsien had already revolutionized the field of calcium sensing. His group’s work helped transform the protein from a coelenterate curiosity to a laboratory staple and earned Tsien a third of the 2008 Nobel Prize in Chemistry. Ironically, Tsien, who died in 2016, is best remembered for his contributions to developing a molecular biology icon: green fluorescent protein. “Early on, he was actually somewhat dismissive of molecular biology.” “His somewhat flippant answer was, ‘Because it cannot be cloned,’” recalled Joseph Kao, who was a postdoc in Tsien’s lab. At a time when cloning a gene was a feat worthy of a high-impact publication, someone asked Roger Tsien why he studied calcium.
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