'Resistance is futile?' - paradoxical inhibitory effects of K-ATP channel closure in glucagon-secreting alpha-cells

• By secreting insulin and glucagon, the beta- and alpha-cells of the pancreatic islets play a central role in the regulation of systemic metabolism. Both cells are equipped with ATP-regulated potassium (K-ATP) channels that are regulated by the intracellular ATP/ADP ratio. In beta-cells, K-ATP channels are active at low (non-insulin-releasing) glucose concentrations. An increase in glucose leads to K-ATP 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 alpha-cells are also equipped with K-ATP channels but they are under strong tonic inhibition at low glucose, explaining why alpha-cells are electrically active under hypoglycaemic conditions and generate large Na+- and Ca2+-dependent action potentials. Closure of residual K-ATP 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 alpha-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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Fysiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Physiology (hsv//eng)

Keyword

diabetes

glucagon

insulin

K(ATP)channels

membrane potential

pancreatic beta-cells

gated ion channels

delta-cells

electrical-activity

insulin-secretion

intact islets

patch-clamp

dependent regulation

mouse islets

b-cells

Neurosciences & Neurology

Physiology

Publication and Content Type

ref (subject category)

art (subject category)