‘Resistance is futile?’ – paradoxical inhibitory effects of K_ATP channel closure in glucagon‐secreting α‐cells

Abstract

By secreting insulin and glucagon, the β‐ and α‐cells of the pancreatic islets play a central role in the regulation of systemic metabolism. Both cells are equipped with ATP‐regulated potassium (KATP) channels that are regulated by the intracellular ATP/ADP ratio. In β‐cells, KATP channels are active at low (non‐insulin‐releasing) glucose concentrations. An increase in glucose leads to KATP channel closure, membrane depolarization and electrical activity that culminates in elevation of [Ca2+]i and initiation of exocytosis of the insulin‐containing secretory granules. The α‐cells are also equipped with KATP channels but they are under strong tonic inhibition at low glucose, explaining why α‐cells are electrically active under hypoglycaemic conditions and generate large Na+‐ and Ca2+‐dependent action potentials. Closure of residual KATP channel activity leads to membrane depolarization and an increase in action potential firing but this stimulation of electrical activity is associated with inhibition rather than acceleration of glucagon secretion. This paradox arises because membrane depolarization reduces the amplitude of the action potentials by voltage‐dependent inactivation of the Na+ channels involved in action potential generation. Exocytosis in α‐cells is tightly linked to the opening of voltage‐gated P/Q‐type Ca2+ channels, the activation of which is steeply voltage‐dependent. Accordingly, the inhibitory effect of the reduced action potential amplitude exceeds the stimulatory effect resulting from the increased action potential frequency. These observations highlight a previously unrecognised role of the action potential amplitude as a key regulator of pancreatic islet hormone secretion.

Calcium Oscillations in Pancreatic α-cells Rely on Noise and ATP-Driven Changes in Membrane Electrical Activity

“…The simulations predict that the number of simultaneously active K ATP channels during electrical activity is between ∼5 and 10, in agreement with experimental observations ( Zhang et al, 2020 ). This number is much smaller than the total number of channels considered in the simulations ( N KATP = 58), which are all potentially openable.…”

“…Plasma membrane ATP-sensitive K + channels (K ATP channels) play a key role in controlling α-cells electrical activity, although the details of this control are still actively debated ( Gilon, 2020 ; Zhang et al, 2020 ). When the amplitude of this current is relatively limited, voltage-gated Na + and Ca 2+ channels can indeed initiate an AP.…”

KATP channel blockers control glucagon secretion by distinct mechanisms: A direct stimulation of α-cells involving a [Ca2+]c rise and an indirect inhibition mediated by somatostatin

“…By contrast, low concentrations of diazoxide which only slightly activate K ATP channels increased [Ca 2+ ] c and stimulated glucagon release [ 21 ]. All these observations led to suggest the recently reviewed model that is based on the idea that sulfonylureas modulate glucagon secretion mainly by a direct action on α-cells [ 71 ]. In the presence of a low glucose concentration, most K ATP channels are already closed (contrary to the situation in β-cells) and α-cells display spontaneous action potentials; the upstroke phase of which involves the activation of Na v and high threshold VGCC (mostly P/Q type).…”

“…The reasons for all these discrepancies are unknown. It has been speculated that it might be because of species differences as mouse, rat, and human α-cells do not express the same sets of channels and might not have the same K ATP channel density [ 13 , 22 , 67 , 69 , 71 , 80 ]. However, this explanation is not sufficient because divergent results were obtained using the same species, the mouse.…”

Vitamin D binding protein/GC‐globulin: a novel regulator of alpha cell function and glucagon secretion

“…By contrast, rising blood glucose levels increase ATP/ADP ratios, causing K ATP channels to close. This further depolarisation leads to partial voltage inactivation of Na + channels, depressing action potential peak amplitude, reducing voltagegated P/Q-Ca 2+ channel activation and thus inhibiting glucagon secretion (Zhang et al, 2013;Zhang et al, 2020) ( Figure 1A). The K ATP channel model of alpha cell regulation remains debated, however, since opposing effects of K ATP channel blockers (sulfonylureas) on glucagon release have been reported (Cheng-Xue et al, 2013;Zhang et al, 2013), including a strong glucagonotropic effect in the absence of somatostatin input (Lai et al, 2018), amongst other arguments.…”