Intercellular calcium waves integrate hormonal control of glucose output in the intact liver

KEY POINTS: Sympathetic outflow and circulating glucogenic hormones both regulate liver function by increasing cytosolic calcium, although how these calcium signals are integrated at the tissue level is currently unknown. We show that stimulation of hepatic nerve fibres or perfusing the liver with physiological concentrations of vasopressin only will evoke localized cytosolic calcium oscillations and modest increases in hepatic glucose production. The combination of these stimuli acted synergistically to convert localized and asynchronous calcium responses into co‐ordinated intercellular calcium waves that spread throughout the liver lobule and elicited a synergistic increase in hepatic glucose production. The results obtained in the present study demonstrate that subthreshold levels of one hormone can create an excitable medium across the liver lobule, which allows global propagation of calcium signals in response to local sympathetic innervation and integration of metabolic regulation by multiple hormones. This enables the liver lobules to respond as functional units to produce full‐strength metabolic output at physiological levels of hormone. ABSTRACT: Glucogenic hormones, including catecholamines and vasopressin, induce frequency‐modulated cytosolic Ca(2+) oscillations in hepatocytes, and these propagate as intercellular Ca(2+) waves via gap junctions in the intact liver. We investigated the role of co‐ordinated Ca(2+) waves as a mechanism for integrating multiple endocrine and neuroendocrine inputs to control hepatic glucose production in perfused rat liver. Sympathetic nerve stimulation elicited localized Ca(2+) increases that were restricted to hepatocytes in the periportal zone. During perfusion with subthreshold vasopressin, sympathetic stimulation converted asynchronous Ca(2+) signals in a limited number of hepatocytes into co‐ordinated intercellular Ca(2+) waves that propagated across entire lobules. A similar synergism was observed between physiological concentrations of glucagon and vasopressin, where glucagon also facilitated the recruitment of hepatocytes into a Ca(2+) wave. Hepatic glucose production was significantly higher with intralobular Ca(2+) waves. We propose that inositol 1,4,5‐trisphosphate (IP(3))‐dependent Ca(2+) signalling gives rise to an excitable medium across the functional syncytium of the hepatic lobule, co‐ordinating and amplifying the metabolic responses to multiple hormonal inputs.