GABA-INDUCED CALCIUM SIGNALING IN THE PRIMARY CILIUM OF NEURONS

The primary cilium is a solitary organelle present in both neurons and astrocytes whose function is to provide a multiplexed and privileged platform interfacing the cells with their environment. What signals it detects and in which ways it affects cellular behavior are largely unanswered questions, although accumulating evidence documents dysregulation of ciliary function in Parkinson’s and Alzheimer’s diseases.
We have established that the metabotropic GABA receptor subtype 1 (GABA-B1) is a bona fide ciliary receptor, not just in neurons but also in a variety of other cells.
Experiments in primary cultures reveal that neuronal cilium is active displaying spontaneous calcium dynamics, the compartment is not affected by cytoplasmic activity.
We also show that GABA-B1 localizes to the base of neuronal cilia in adult mouse brain sections across different regions, with the strongest enrichment in striatal cilia. Interestingly, the receptor is absent from astrocytic cilia though motile cilia of ependymal cells and upper airway epithelium are positive.
Finally, activation of GABA-B1 receptors with the agonist baclofen (100nM) drives calcium signaling that is restricted to the cilium.
We have recently shown a GABA-B1 ciliary pathway operating in pancreatic BETA-cells engaging non-canonical downstream partners to trigger calcium transients, notably without forming an hetero-dimer with the cognate GABA-B2 receptor.
We suggest that this novel GABAergic ciliary pathway with excitatory features is conserved in a variety of ciliated cell types, furthermore in neurons it provides a parallel input adjoining the known actions of GABA as the major inhibitory neurotransmitter in the mature brain.