Regulation of β-cell function through the primary cilium

Primary cilia are rod-like sensory organelles extending from the surface of most mammalian cells, and recent studies indicate they play critical roles in islet cell function and hormone secretion. Their sensory ability is achieved by specific receptors that initiate signal transduction within the cilium, enabling localized signaling events that can propagate into the cell and modulate its function. Using intact mouse and human islets, we show that GABA and somatostatin, two major paracrine factors in the islet microenvironment, exert their effects through ciliary receptors. We found that GABAB1 receptors were enriched at the ciliary base, but mobilized distally upon GABA binding and selectively induced ciliary Ca²+ influx via activation of voltage-dependent Ca²+ channels. At the same time, cytosolic Ca²+ increases were prevented from propagating into the cilium due to enhanced Ca²+ extrusion at the cilia base, thus isolating the cilium from cytosolic Ca2+ signals. Somatostatin, secreted from islet δ-cells, directly activated ciliary SSTR3 receptors on neighboring β-cells as a consequence of their close proximity within the islet microenvironment. This localized signaling resulted in a rapid reduction of cAMP specifically within the cilium, promoting sustained nuclear entry of the cilia-dependent transcription factor GLI2. This mechanism operated in parallel with the canonical Hedgehog pathway and was critically dependent on ciliary Ca2+ signaling. We further showed that somatostatin was released directly onto β-cell cilia in intact islets, establishing primary cilia as a key site for paracrine regulation of β-cell function. Islets isolated from patients with type-2 diabetes were found to contain cells with reduced cilia length, which in turn led to reduced proximity between β-cell cilia and islet δ-cells. Additionally, cGMP was identified as another important ciliary second messenger. Both GLP-1 and atrial natriuretic peptide stimulated cGMP formation in β-cells, and the nucleotide freely diffused into the cilium, where it triggered increases in Ca2+ at least in part through activation of cyclic nucleotide-gated channels. Moreover, cGMP increases, similar to cAMP reductions, induced stable nuclear translocation of GLI2, indicating intricate interdependence of cAMP and cGMP signaling that may converge on ciliary Ca2+. These findings highlight the primary cilium as a specialized and unique signaling compartment for integrating and interpreting paracrine, endocrine and intracellular cues, with important implications for islet cell function.