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

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 α ₁ and α ₂ adrenergic receptors, whereas β receptors triggered only cAMP responses. The α 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 α ₁A and α 1D receptors are key targets for phenylephrine, acting through Ca²⁺/calmodulin-dependent adenylyl cyclases AC1 and AC3 downstream of α ₁ receptor activation. Moreover, α ₂ receptor stimulation raised Ca²⁺ levels, thereby stimulating cAMP production, yet also reduced forskolin-induced cAMP elevations, indicating that α ₂ receptors can both inhibit adenylyl cyclase via G i 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.