Controlling insulin secretion: an exciting TASK.

Abstract

The -cells of the pancreatic islets of Langerhans secrete insulin in response to metabolic fuels and neurohormonal inputs after a meal. The proper regulation of insulin secretion is critical for the maintenance of glucose homeostasis. An absolute or relative impairment of insulin secretion in the face of insulin resistance underlies the pathophysiology of type 2 diabetes. Accordingly, some of the key antidiabetes agents promote increased insulin secretion from islets, including the newer incretin-based therapeutics and the sulfonylurea class of drugs. The consensus mechanism for glucose-stimulated insulin secretion was elucidated almost 30 years ago and has remained largely unchanged since. A glucose-dependent increase in the intracellular ATP to ADP ratio closes ATP-sensitive potassium (KATP) ion channels (1, 2), themselves the target of the sulfonylurea drugs (3). This results in depolarization of the -cell membrane and the firing of action potentials, which allows the activation of voltage-gated Ca channels and a rise in intracellular Ca that triggers insulin release (4). It is well-recognized, however, that a diverse array of additional ion channels contribute to -cell excitability, and only recently have we begun to understand the roles and molecular identities of the many key channels that shape the electrical response in these cells. Although the outward flux of K mediated by KATP channels dominates the electrical conductance of the -cell membrane in the resting condition,holding themembranepotential of these cells near the equilibrium potential for K ( 70 mV), closure of KATP channels upon glucose stimulation is not in itself sufficient to depolarize the cell. For the -cell to depolarize, an inward depolarizing leak current is required to push the membrane potential toward a more positive equilibrium (or plateau, Figure 1) sufficient to allow the activation of the voltage-gated Na , Ca , and K channels that mediate regenerative action potential firing (5). This depolarizing force is likely mediated by channels that mainly allow the inward leak of Na (and possibly Ca ) such as the transient receptor potential (TRP) family of channels (6) and/or the muscarinic-activated nonselective Na -leak channel (NALNC) (7). Additional currents, such as those mediated by the smallconductance Ca -sensitive K (SK) channels (8) and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels (9), contribute to the oscillatory nature of the electrical activity that characterizes -cell electrical function. Although required for membrane depolarization after glucose stimulation, these inward leak currents pose a problem of their own: the equilibrium potential for Na and Ca is much too positive ( 50 mV) to allow the rhythmic opening and closing of voltage-dependent ion channels required for action potential firing. What this means is that upon KATP channel closure in response to elevated glucose or sulfonylurea, the inward leak currents could depolarize the -cell too much, unless a counterbalancing outward leak is also present. In the present issue of Endocrinology, Dadi et al (10) present evidence to suggest that this key outward leak current is mediated by TASK-1, a member of the 2-poredomain K (K2P) channel family shown to be expressed at the mRNA level in human -cells only very recently (11, 12) and suggested previously as a target of inhaled anesthetics (13) and for the treatment of multiple sclerosis (14), T cell-mediated autoimmunity (15), and cardiac arrhythmia (16) among other conditions. Using cell-type–specific knockout mice and a selective TASK-1 inhibitor, the authors demonstrate that this channel mediates a back-