Editing Alpha cell (section)

== Regulation of glucagon secretion ==
There are several methods of control of the secretion of glucagon. The most well studied is through the action of extra-pancreatic glucose sensors, including neurons found in the brain and spinal cord, which exert control over the alpha cells in the pancreas.<ref name=":3" /> Indirect, non-neuronal control has also been found to influence secretion of glucagon.<ref name=":3" />

=== Neuronal Control ===
The most well studied is through the action of extra-pancreatic glucose sensors, including neurons found in the brain, which exert control over the alpha cells in the pancreas.<ref name=":3" /> The pancreas is controlled by both the [[sympathetic nervous system]] and the [[parasympathetic nervous system]], although the method these two systems use to control the pancreas appears to be different.<ref name=":5">{{Cite journal |last1=Verberne |first1=Anthony J. M. |last2=Mussa |first2=Bashair M. |date=2022-06-01 |title=Neural control of pancreatic peptide hormone secretion |url=https://www.sciencedirect.com/science/article/pii/S0196978122000341 |journal=Peptides |language=en |volume=152 |pages=170768 |doi=10.1016/j.peptides.2022.170768 |pmid=35189258 |s2cid=246906606 |issn=0196-9781|url-access=subscription }}</ref>

Sympathetic control of the pancreas appears to originate from the sympathetic preganglionic fibers in the lower thoracic and lumbar spinal cord.<ref name=":6">{{Cite journal |first1=Tanja |last1=Babic |first2=R. Alberto |last2=Travagli |date=2016-09-23 |title=Neural Control of the Pancreas |url=https://pancreapedia.org/reviews/neural-control-of-pancreas |journal=Pancreapedia: The Exocrine Pancreas Knowledge Base |language=en |doi=10.3998/panc.2016.27|doi-access=free }}</ref> According to Travagli et al. "axons from these neurons exit the spinal cord through the [[Ventral root of spinal nerve|ventral roots]] and supply either the [[paravertebral ganglia]] of the sympathetic chain via communicating rami of the thoracic and lumbar nerves, or the celiac and mesenteric ganglia via the [[splanchnic nerves]]. The catecholaminergic neurons of these ganglia innervate the intrapancreatic ganglia, islets and blood vessels..."<ref name=":6" /> The exact nature of the effect of sympathetic activation on the pancreas has been difficult to discern. However, a few things are known. It appears that stimulation of the splanchnic nerve lowers plasma insulin levels possibly through the action of α2 adrenoreceptors on beta cells.<ref name=":6" /> It has also been shown that stimulation of the splanchnic nerve increases glucagon secretion.<ref name=":6" /> Both of these findings together suggest that sympathetic stimulation of the pancreas is meant to maintain blood glucose levels during heightened arousal.<ref name=":6" />

Parasympathetic control of the pancreas appears to originate from the [[Vagus nerve]].<ref name=":5" /> Electrical and pharmacological stimulation of the Vagus nerve increases secretion of glucagon and insulin in most mammalian species, including humans. This suggests that the role of parasympathetic control is to maintain normal blood glucose concentration under normal conditions.<ref name=":5" />

=== Non-neuronal Control ===
Non-neuronal control has been found to be indirect [[Paracrine signaling|paracrine]] regulation through ions, hormones, and neurotransmitters. Zinc, insulin, [[serotonin]], [[Gamma-Aminobutyric acid|γ-aminobutyric acid]], and [[Gamma-Hydroxybutyric acid|γ-hydroxybutyrate]], all of which are released by [[beta cell]]s in the pancreas, have been found to suppress glucagon production in alpha cells.<ref name=":3" /> [[Delta cell]]s also release [[somatostatin]] which has been found to inhibit glucagon secretion.<ref name=":3" />

Zinc is secreted at the same time as insulin by the beta cells in the pancreas. It has been proposed to act as a paracrine signal to inhibit glucagon secretion in alpha cells. Zinc is transported into both alpha and beta cells by the zinc transporter [[Zinc transporter 8|ZnT8]]. This protein channel allows zinc to cross the plasma membrane into the cell. When ZnT8 is under-expressed, there is a marked increase in glucagon secretion. When ZnT8 is over-expressed, there is a marked decrease in glucagon secretion. The exact mechanism by which zinc inhibits glucagon secretion is not known.<ref>{{Cite journal |last1=Rutter |first1=Guy A. |last2=Chabosseau |first2=Pauline |last3=Bellomo |first3=Elisa A. |last4=Maret |first4=Wolfgang |last5=Mitchell |first5=Ryan K. |last6=Hodson |first6=David J. |last7=Solomou |first7=Antonia |last8=Hu |first8=Ming |date=February 2016 |title=Intracellular zinc in insulin secretion and action: a determinant of diabetes risk? |journal=Proceedings of the Nutrition Society |language=en |volume=75 |issue=1 |pages=61–72 |doi=10.1017/S0029665115003237 |pmid=26365743 |s2cid=13936539 |issn=0029-6651|doi-access=free }}</ref>

Insulin has been shown to function as a paracrine signal to inhibit glucagon secretion by the alpha cells.<ref>{{Cite journal |last1=Asplin |first1=C. M. |last2=Paquette |first2=T. L. |last3=Palmer |first3=J. P. |date=1981-07-01 |title=In vivo inhibition of glucagon secretion by paracrine beta cell activity in man. |url=https://www.jci.org/articles/view/110251 |journal=The Journal of Clinical Investigation |language=en |volume=68 |issue=1 |pages=314–318 |doi=10.1172/JCI110251 |issn=0021-9738 |pmc=370801 |pmid=7019246}}</ref> However, this is not through a direct interaction. It appears that insulin functions to inhibit glucagon secretion through activation of delta cells to secrete somatostatin.<ref name=":7">{{Cite journal |last1=Vergari |first1=Elisa |last2=Knudsen |first2=Jakob G. |last3=Ramracheya |first3=Reshma |last4=Salehi |first4=Albert |last5=Zhang |first5=Quan |last6=Adam |first6=Julie |last7=Asterholm |first7=Ingrid Wernstedt |last8=Benrick |first8=Anna |last9=Briant |first9=Linford J. B. |last10=Chibalina |first10=Margarita V. |last11=Gribble |first11=Fiona M. |date=2019-01-11 |title=Insulin inhibits glucagon release by SGLT2-induced stimulation of somatostatin secretion |journal=Nature Communications |language=en |volume=10 |issue=1 |pages=139 |doi=10.1038/s41467-018-08193-8 |issn=2041-1723 |pmc=6329806 |pmid=30635569|bibcode=2019NatCo..10..139V }}</ref> Insulin binds to [[Sodium/glucose cotransporter 2|SGLT2]] causing an increased glucose uptake into delta cells. SGLT2 is a sodium and glucose [[symporter]], meaning that it brings glucose and sodium ions across the membrane at the same time in the same direction. This influx of sodium ions, in the right conditions, can cause a depolarization event across the membrane. This opens calcium channels, causing intracellular calcium levels to increase. This increase in the concentration of calcium in the cytosol activates [[ryanodine receptor]]s on the [[endoplasmic reticulum]] which causes the release of more calcium into the cytosol. This increase in calcium causes the secretion of somatostatin by the delta cells.<ref name=":7" />

Somatostatin inhibits glucagon secretion through the activation of [[Somatostatin receptor 2|SSTR2]], a membrane bound protein that when activated causes a hyperpolarization of the membrane. This hyperpolarization causes voltage gated calcium channels to close, leading to a decrease in intracellular calcium levels. This causes a decrease in exocytosis. In the case of alpha cells, this causes a decrease in the secretion of glucagon.<ref>{{Cite journal |last1=Kailey |first1=Balrik |last2=van de Bunt |first2=Martijn |last3=Cheley |first3=Stephen |last4=Johnson |first4=Paul R. |last5=MacDonald |first5=Patrick E. |last6=Gloyn |first6=Anna L. |last7=Rorsman |first7=Patrik |last8=Braun |first8=Matthias |date=2012-11-01 |title=SSTR2 is the functionally dominant somatostatin receptor in human pancreatic β- and α-cells |journal=American Journal of Physiology. Endocrinology and Metabolism |language=en |volume=303 |issue=9 |pages=E1107–E1116 |doi=10.1152/ajpendo.00207.2012 |issn=0193-1849 |pmc=3492856 |pmid=22932785}}</ref>

Serotonin inhibits the secretion of glucagon through its receptors on the plasma membrane of alpha cells. Alpha cells have [[5-HT1F receptor|5-HT1f receptors]] which are triggered by the binding of serotonin. Once activated, these receptors suppress the action of adenylyl cyclase, which suppresses the production of cAMP. The inhibition of the production of cAMP in turn suppresses the secretion of glucagon.<ref name=":3" /> Serotonin is considered a paracrine signal due to the close proximity of beta cells to alpha cells.<ref>{{Cite journal |last1=Almaça |first1=Joana |last2=Molina |first2=Judith |last3=Menegaz |first3=Danusa |last4=Pronin |first4=Alexey N. |last5=Tamayo |first5=Alejandro |last6=Slepak |first6=Vladlen |last7=Berggren |first7=Per-Olof |last8=Caicedo |first8=Alejandro |date=2016-12-20 |title=Human Beta Cells Produce and Release Serotonin to Inhibit Glucagon Secretion from Alpha Cells |journal=Cell Reports |language=English |volume=17 |issue=12 |pages=3281–3291 |doi=10.1016/j.celrep.2016.11.072 |issn=2211-1247 |pmc=5217294 |pmid=28009296}}</ref>

Glucose can also have a somewhat direct influence on glucagon secretion as well. This is through the influence of ATP. Cellular concentrations of ATP directly reflects the concentration of glucose in the blood. If the concentration of ATP drops in alpha cells, this causes potassium ion channels in the plasma membrane to close. This causes depolarization across the membrane causing calcium ion channels to open, allowing calcium to flood into the cell. This increase in the cellular concentration of calcium causes secretory vesicles containing glucagon to fuse with the plasma membrane, thus causing the secretion of glucagon from the pancreas.<ref name=":3" />