Crosstalk of noradrenergic Ca2+ and cAMP signaling in astrocytes of the murine olfactory bulb

Abstract

Cyclic adenosine monophosphate (cAMP) and Ca2+ are ubiquitous second messengers that regulate gene expression, metabolism, and synaptic plasticity. Here, we identified a complex interplay between Ca2+ and cAMP signaling pathways in mouse olfactory bulb astrocytes. Norepinephrine (NE) elevated both Ca2+ and cAMP levels via 1 and 2 adrenergic receptors, whereas {beta} receptors triggered only cAMP responses. The 1 receptor agonist phenylephrine increased cAMP, but this effect was suppressed when Ca2+ elevations were blocked by Ca2+ depletion and removal of external Ca2+. We found that 1A and 1D receptors are key targets for phenylephrine, acting through Ca2+/calmodulin-dependent adenylyl cyclases AC1 and AC3 downstream of 1 receptor activation. Moreover, 2 receptor stimulation raised Ca2+ levels, thereby stimulating cAMP production, yet also reduced forskolin-induced cAMP elevations, indicating that 2 receptors can both inhibit adenylyl cyclase via Gi and stimulate AC1/AC3 via Ca2+ signaling. Together, these findings reveal intricate crosstalk between noradrenergic Ca2+ and cAMP signaling in olfactory bulb astrocytes mediated by all three adrenergic receptor subtypes.