Norepinephrine-induced intracellular Ca²⁺ increase is coupled with astrocytic BK channel activation and capillary response

Astrocytes are abundant glial cells organized in a meshwork in which each cell is in contact with both neuronal and vascular elements. They receive and respond to neuronal signals and modulate synaptic activity and diameter of blood vessels through changes in their intracellular Ca²⁺. Norepinephrine plays an important role in both of these astrocytic functions; however, it remains unclear whether norepinephrine-induced intracellular Ca²⁺ increase leads to further cellular adjustments in astrocyte activity. Here, we reveal a causal relationship between norepinephrine-induced intracellular Ca²⁺ increase, α1-adrenergic receptor activation and activation of large-conductance Ca²⁺-dependent potassium ion (BK) channel in cultured rat cortical astrocytes. BK channel activation was abolished by α1-adrenergic receptor blockade, depletion of intracellular Ca²⁺ stores, or dialysis of astrocytes with a Ca²⁺ chelator. We further show that this norepinephrine-induced astrocytic Ca²⁺-BK channel coupling contributes to a reduction in cortical capillary diameter. The capillary response was prevented by pharmacological silencing of astrocytes or BK channel blockade, whereas the norepinephrine effect was mimicked by direct BK channel activation with an agonist in acute brain slices. In summary, these results elucidate a previously unrecognized cellular response of astrocytes to norepinephrine that is coupled with modulation of capillary diameter and may represent an integral part of the astrocytic communication with neurons and blood vessels.<b>NEW & NOTEWORTHY</b> This study reveals adjustments of astrocyte activity in response to neurotransmitter norepinephrine. We provide compelling demonstration that norepinephrine-induced intracellular Ca²⁺ increase is coupled with BK channel activation in cultured cortical astrocytes. Our results further indicate that norepinephrine-induced astrocytic Ca²⁺-BK channel signaling participates in modulation of capillary diameter in the cortex. These findings provide better understanding of astrocyte communication with neurons and blood vessels.