Calcium Signalling in Liver Cells

Abstract

In hepatocytes, increases in the concentration of Ca²⁺ in the cytoplasmic space and mitochondrial matrix play central roles in the regulation by hormones, neurotransmitters and growth factors of metabolic pathways, the secretion of bile acids, cell growth, and the metabolism of drugs and toxic agents. One of several important forms of intracellular Ca²⁺ signal is the hormone-induced wave of increased cytoplasmic Ca²⁺ concentration which begins at the canalicular membrane and moves to the sinusoidal membrane in an individual hepatocyte, and travels between neighbouring hepatocytes via gap junctions. The nature of this Ca²⁺ signal is, in part, a product of the polarised structure of the hepatocyte. This structure also has an important bearing on the process by which the Ca²⁺ wave is generated. The maintenance of successive waves of increased cytoplasmic Ca²⁺ concentration involves the inositol 1,4,5-trisphosphate and ryanodine Ca²⁺ channels in the endoplasmic reticulum, Ca²⁺ channels and transporters in the mitochondria, a variety of plasma membrane Ca²⁺ channels and the plasma membrane (Ca²⁺ + Mg²⁺)ATP-ase, GTP-binding regulatory proteins and the cytoskeleton. Glucagon, in the presence of a hormone which generates inositol 1,4,5-trisphosphate, causes a profound stimulation of Ca²⁺ inflow and increases the mitochondrial Ca²⁺ concentration. The latter contributes to the regulation of mitochondrial ATP synthesis. Changes or abnormalities in the intracellular Ca²⁺ signalling pathways in hepatocytes may underlie a number of diseased states, including some forms of cholestasis, and the response of the liver to toxic insults.