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.
Highlights
In most cells, potassium (K+) channel activity constitutes the principal background membrane conductance, which explains why the resting membrane potential usually approximates the K+ equilibrium potential (EK; ß-70 mV)
When KATP channel activity is instead measured in α-cells in acutely isolated intact islets, the resting membrane conductance was found to be 270 pS at 1 mM glucose and reduced to ß200 pS after application of tolbutamide or increasing glucose to 6 mM (Zhang et al 2013)
It is implicit from the model that exocytosis of the glucagon granules is regulated by [Ca2+]i close to the inner mouth of the P/Q-type Ca2+ channels. This is supported by the findings that exocytosis is resistant to intracellular application of millimolar concentrations of the Ca2+ chelator EGTA (Zhang et al 2013). It remains an open question whether hyperglycaemia inhibits glucagon secretion exclusively by the same mechanism or whether glucose metabolism modulates P/Q-type Ca2+ channel activity by a more direct inhibitory effect
Summary
Potassium (K+) channel activity constitutes the principal background membrane conductance, which explains why the resting membrane potential usually approximates the K+ equilibrium potential (EK; ß-70 mV). ATP-sensitive potassium (KATP) channels are expressed in a number of cells including cardiomyocytes, skeletal muscle, smooth muscle cells and certain neurones (Huang et al 2019) Their role is evident in the β-cells of the pancreatic islets (Ashcroft, 2007). Insulin and glucagon are the body’s principal glucose-regulating hormones (Frayn & Evans, 2019) They are released in response to increases (hyperglycaemia) and decreases (hypoglycaemia) in plasma glucose concentrations, respectively. Given the reciprocal regulation of insulin and glucagon secretion by glucose, the question arises as to how KATP channel closure stimulates secretion in β-cells but inhibits it in α-cells. In this Topical Review we consider this conundrum
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