Abstract
Cells coordinate their activities with the outside world by transmitting information across the plasma membrane. An increase in intracellular calcium ion (Ca2+) concentration is one of the most common signals used to link extracellular events to changes in intracellular activity. These Ca2+ signals are invariably generated by regulated opening of Ca2+-permeable channels, through which Ca2+ can flow rapidly down steep concentration gradients into the cytosol. Inositol 1,4,5-trisphosphate receptors (IP3R) are ubiquitous intracellular channels that mediate release of Ca2+ from intracellular stores. Binding of inositol trisphosphate (IP3) to an IP3Rs primes it to respond to Ca2+, which then triggers opening of the channel. This allows IP3Rs to regeneratively propagate intracellular Ca2+ signals. This regenerative property and the observation that local Ca2+ signals selectively regulate different intracellular responses highlight the need to understand the relationship between the subcellular geography of IP3Rs and the responses they evoke. In this lecture, the speaker will briefly discuss how IP3 binding initiates IP3R activation; the importance of intimate interactions between other organelles and IP3Rs within the endoplasmic reticulum (ER) in determining functional responses; and finally consider his very recent work using super-resolution microscopy to record the geography of endogenously tagged IP3Rs while simultaneously observing the Ca2+ signals they evoke. The latter shows that native IP3Rs form loose clusters, each including about 8 tetrameric IP3Rs. Most IP3R clusters are mobile, moved by diffusion and microtubule motors. Although only a third of IP3R clusters are immobile, and only a small fraction of these lie close to the plasma membrane, the Ca2+ puffs evoked by histamine or photolysis of caged-IP3 are entirely mediated by these IP3Rs. Hence, these IP3Rs are ‘licensed’ to respond, but they do not readily mix with mobile IP3Rs. The licensed IP3Rs reside alongside ER-plasma membrane junctions, where the proteins that regulate store-operated Ca2+ entry accumulate after depletion of Ca2+ stores. Our results suggest that IP3Rs tethered close to ER-plasma membrane junctions are licensed to respond and optimally placed to be activated by endogenous IP3 and to regulate Ca2+ entry.
About the speaker
Prof Colin W Taylor studied Natural Sciences at Gonville and Caius College and completed a PhD in insect physiology at the University of Cambridge in 1984. He then carried out his postdoctoral work at the Medical College of Virginia. After that, he returned to the University of Cambridge as a research fellow of St John’s College and a Royal Society Locke Research Fellow. He was appointed a lecturer of Pharmacology there in 1989, and later a Lister Institute Research Fellow in 1992, before he rose to become Reader and then Professor of Cellular Pharmacology in 1995 and 2001.
Prof Taylor’s primary research focus is on calcium signaling. A prolific author with more than 200 publications, he also served as editor to Biochemical Journal (2002-10) and Pharmacology and Therapeutics (1989-1995). As editor, he also contributed to Neuromoethods and The International Encyclopedia of Pharmacology and Therapeutics – Intracellular Messengers.
Prof Taylor is a member of Academia Europaea, a Fellow of the Academy of Medical Sciences, and a Wellcome Trust Senior Investigator. He has also been the member of Lister Institute since 1998 and the Molecular and Cellular Medicine Board member of Medical Research Council since 2015.
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