{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T07:31:16Z","timestamp":1767943876947,"version":"3.49.0"},"reference-count":96,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,11,22]],"date-time":"2025-11-22T00:00:00Z","timestamp":1763769600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>\n                      Cholinergic input initiates or regulates prolonged neuronal activity implicated in executive attention, learning and neuroendocrine control. In the hermaphroditic sea snail,\n                      <jats:italic>Aplysia<\/jats:italic>\n                      , ionotropic acetylcholine receptors on neuroendocrine bag cell neurons trigger an \u223c30\u2010min afterdischarge that leads to egg\u2010laying hormone secretion and reproductive behaviour. The afterdischarge is followed by an \u223c18\u2010h refractory period, where acetylcholine fails to cause further bursting. Here, we report on a similar long\u2010term depression of acetylcholine receptors in cultured bag cell neurons. Under whole\u2010cell voltage\u2010clamp, the current evoked by 2\u2010s pressure\u2010ejections of 1\u00a0mM acetylcholine exhibited persistent rundown, with partial recovery by 6 h after the first ejection and complete recovery at 24\u00a0h. Consecutive applications at 3\u2010, 10\u2010, 30\u2010, 60\u2010 or 90\u2010min intervals reliably yielded \u223ctwo\u2010thirds of current remaining at the second ejection. Similar rundown was elicited using the cholinergic agonist tretramethylammonium, albeit at 10\u00a0mM. Rundown was independent of channel gating, as the acetylcholine receptor pore\u2010blocker hexamethonium failed to alter progression. Neither the protein kinase A blocker KT5720 nor the muscarinic receptor antagonist phenyltrimethylammonium affected rundown. However, the proteasome inhibitor lactacystin attenuated rundown, while disrupting the\n                      <jats:italic>trans<\/jats:italic>\n                      \u2010Golgi network with brefeldin A or protein synthesis with anisomcyin prevented recovery 24\u00a0h later, consistent with receptor trafficking underlying both rundown and recovery. A decrease in receptor membrane density following acetylcholine was confirmed by confocal microscopy of neurons stained with the dye\u2010conjugated ionotropic antagonist \u2010conotoxin ImI\u2010ATTO Fluor\u2010590. Hence, retrieval of receptors from the membrane mediates rundown and, analogous to the refractory period, may control the timing of reproduction.\n                      <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                        <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp70230-gra-0001-m.png\">\n                          <jats:alt-text>image<\/jats:alt-text>\n                        <\/jats:graphic>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>\n                            Hormone secretion from neuroendocrine cells typically requires a prolonged burst of action potentials; for example, bag cell neurons from the marine snail\n                            <jats:italic>Aplysia<\/jats:italic>\n                            trigger reproduction by the neurohaemal release of egg\u2010laying hormone during a lengthy afterdischarge.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>The bag cell neuron afterdischarge is initiated by cholinergic synaptic input onto ionotropic acetylcholine receptors, but following an afterdischarge, the neurons become unresponsive to acetylcholine for many hours.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>We now demonstrate that, after an initial exposure to acetylcholine, a proportion of these ionotropic receptors are internalized and made unavailable, without any influence from a metabotropic counterpart.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>This prolonged depression of cholinergic receptors also lasts many hours and likely serves to prevent disruption of ongoing bursting and\/or the amount of hormone released.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Therefore, changes in the number of ionotropic receptors at the membrane may influence the timing of neuroendocrine cell activity.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  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