Anne Elizabeth Warner. 25 August 1940—16 May 2012

Anne Warner applied physiological techniques to developmental biology, elucidating the mechanisms of cell interaction and communication that pattern the early embryo. Through her determination and passion for science, she contributed crucial discoveries in the fields of muscle physiology, cellular differentiation and gap junction communication. She spent the majority of her career at University College London, which became her intellectual home and where she acquired a Royal Society Foulerton Research Professorship, becoming a highly respected and influential figure. In her work on gap junctions, Anne was the first to show that embryonic development and patterning required gap junctions, and that the restriction of junctional communication between cells played a key role in tissue differentiation. Anne excelled in her breadth of vision across research and its interdisciplinary possibilities. In 1998 she established the CoMPLEX Centre for systems biology at UCL, bringing her own group together with scientists from across the STEM subjects to build testable mathematical models of biological systems across multiple scales. Indefatigable in her capacity for leadership and committee work, she assumed an eclectic set of roles across a large span of research organizations and professional societies, and had a lifelong association with the Physiological Society. In 1984 she founded the Microelectrodes course at the Plymouth Marine Biology Laboratory, which has trained generations in the art of electrophysiology and still continues today. With uncompromisingly high standards, she inspired her mentees to be ambitious and fearless, and established postdoctoral fellowships to help the young scientists who followed after her.

Ethanol Disrupts Hormone-Induced Calcium Signaling in Liver

Receptor-coupled phospholipase C (PLC) is an important target for the actions of ethanol. In the ex vivo perfused rat liver, concentrations of ethanol >100 mM were required to induce a rise in cytosolic calcium (Ca2+) suggesting that these responses may only occur after binge ethanol consumption. Conversely, pharmacologically achievable concentrations of ethanol (≤30 mM) decreased the frequency and magnitude of hormone-stimulated cytosolic and nuclear Ca2+ oscillations and the parallel translocation of protein kinase C-β to the membrane. Ethanol also inhibited gap junction communication resulting in the loss of coordinated and spatially organized intercellular Ca2+ waves in hepatic lobules. Increasing the hormone concentration overcame the effects of ethanol on the frequency of Ca2+ oscillations and amplitude of the individual Ca2+ transients; however, the Ca2+ responses in the intact liver remained disorganized at the intercellular level, suggesting that gap junctions were still inhibited. Pretreating hepatocytes with an alcohol dehydrogenase inhibitor suppressed the effects of ethanol on hormone-induced Ca2+ increases, whereas inhibiting aldehyde dehydrogenase potentiated the inhibitory actions of ethanol, suggesting that acetaldehyde is the underlying mediator. Acute ethanol intoxication inhibited the rate of rise and the magnitude of hormone-stimulated production of inositol 1,4,5-trisphosphate (IP3), but had no effect on the size of Ca2+ spikes induced by photolysis of caged IP3. These findings suggest that ethanol inhibits PLC activity, but does not affect IP3 receptor function. We propose that by suppressing hormone-stimulated PLC activity, ethanol interferes with the dynamic modulation of [IP3] that is required to generate large, amplitude Ca2+ oscillations.

Small subpopulations of β-cells do not drive islet oscillatory [Ca2+] dynamics via gap junction communication

The islets of Langerhans exist as a multicellular network that is important for the regulation of blood glucose levels. The majority of cells in the islet are insulin-producing β-cells, which are excitable cells that are electrically coupled via gap junction channels. β-cells have long been known to display heterogeneous functionality. However, due to gap junction electrical coupling, β-cells show coordinated [Ca2+] oscillations when stimulated with glucose, and global quiescence when unstimulated. Small subpopulations of highly functional β-cells have been suggested to control the dynamics of [Ca2+] and insulin release across the islet. In this study, we investigated the theoretical basis of whether small subpopulations of β-cells can disproportionality control islet [Ca2+] dynamics. Using a multicellular model of the islet, we generated continuous or bimodal distributions of β-cell heterogeneity and examined how islet [Ca2+] dynamics depended on the presence of cells with increased excitability or increased oscillation frequency. We found that the islet was susceptible to marked suppression of [Ca2+] when a ∼10% population of cells with high metabolic activity was hyperpolarized; where hyperpolarizing cells with normal metabolic activity had little effect. However, when these highly metabolic cells were removed from the islet model, near normal [Ca2+] remained. Similarly, when ∼10% of cells with either the highest frequency or earliest elevations in [Ca2+] were removed from the islet, the [Ca2+] oscillation frequency remained largely unchanged. Overall these results indicate that small populations of β-cells with either increased excitability or increased frequency, or signatures of [Ca2+] dynamics that suggest such properties, are unable to disproportionately control islet-wide [Ca2+] via gap junction coupling. As such, we need to reconsider the physiological basis for such small β-cell populations or the mechanism by which they may be acting to control normal islet function.Author summaryMany biological systems can be studied using network theory. How heterogeneous cell subpopulations come together to create complex multicellular behavior is of great value in understanding function and dysfunction in tissues. The pancreatic islet of Langerhans is a highly coupled structure that is important for maintaining blood glucose homeostasis. β-cell electrical activity is coordinated via gap junction communication. The function of the insulin-producing β-cell within the islet is disrupted in diabetes. As such, to understand the causes of islet dysfunction we need to understand how different cells within the islet contribute to its overall function via gap junction coupling. Using a computational model of β-cell electrophysiology, we investigated how small highly functional β-cell populations within the islet contribute to its function. We found that when small populations with greater functionality were introduced into the islet, they displayed signatures of this enhanced functionality. However, when these cells were removed, the islet, retained near-normal function. Thus, in a highly coupled system, such as an islet, the heterogeneity of cells allows small subpopulations to be dispensable, and thus their absence is unable to disrupt the larger cellular network. These findings can be applied to other electrical systems that have heterogeneous cell populations.