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The primary cilium is an organelle present in most adult mammalian cells that is considered as an antenna for sensing the local microenvironment. Here, we use intact mouse pancreatic islets of Langerhans to investigate signaling properties of the primary cilium in insulin-secreting β-cells. We find that GABAB1 receptors are strongly enriched at the base of the cilium, but are mobilized to more distal locations upon agonist binding. Using cilia-targeted Ca2+ indicators, we find that activation of GABAB1 receptors induces selective Ca2+ influx into primary cilia through a mechanism that requires voltage-dependent Ca2+ channel activation. Islet β-cells utilize cytosolic Ca2+ increases as the main trigger for insulin secretion, yet we find that increases in cytosolic Ca2+ fail to propagate into the cilium, and that this isolation is largely due to enhanced Ca2+ extrusion in the cilium. Our work reveals local GABA action on primary cilia that involves Ca2+ influx and depends on restricted Ca2+ diffusion between the cilium and cytosol.

Somatostatin, released from δ-cells within pancreatic islets of Langerhans, is one of the most important negative regulators of islet hormone secretion. We find that islet δ-cells are positioned near, and release somatostatin onto, primary cilia of the other islet cell types, including insulin-secreting β-cells. Somatostatin activates ciliary somatostatin receptors, resulting in rapid lowering of the ciliary cAMP concentration which in turn promotes more sustained nuclear translocation of the cilia-dependent transcription factor GLI2 through a mechanism that operates in parallel with the canonical Hedgehog pathway and depends on ciliary Ca²⁺ signaling. We also find that primary cilia length is reduced in islets from human donors with type-2 diabetes, which is associated with a reduction in interactions between δ-cells and cilia. Our findings show that islet cell primary cilia constitute an important target of somatostatin action, which endows somatostatin with the ability to regulate islet cell function beyond acute suppression of hormone release.

 The cyclic nucleotides cAMP and cGMP are both important second messengers, generated through distinct mechanisms but exhibiting extensive downstream crosstalk. cAMP is a potent amplifier of insulin secretion in pancreatic beta cells, and drugs that promote cAMP formation are therefore in clinical use for the treatment of diabetes. If cGMP changes contribute to these effects is not known. Using isolated human islets and live cell recordings of intracellular cGMP, we now show that both glucose and GLP-1 stimulate the formation of cGMP. The production of cGMP was also stimulated by elevations of the cytosolic Ca²⁺ concentration, and activation of transmembrane guanylate cyclases with atrial natriuretic peptide (ANP) also potently increased cGMP and amplified the response to glucose. cAMP signaling is often compartmentalized, and one important compartment is the primary cilium. We now show that ANP stimulation increases cGMP inside primary cilia, triggering localized increases in the ciliary Ca²⁺ concentration and activating the cilia-dependent transcription factor GLI2, which translocates into the nucleus. These findings identify cGMP as an important second messenger in human beta cells and show that the primary cilium may be an important target of cGMP action in these cells.