Pulmonary neuroepithelial bodies (NEBs) are densely innervated groups of neuroendocrine cells, shielded from the airway lumen by Clara‐like cells (CLCs). In ex vivo mouse lung slices, NEB cells respond with a [Ca²⁺]_i rise to stimulation with high K⁺, followed by a delayed [Ca²⁺]_i increase in CLCs, indicative of an indirect activation. Aim was to unravel the mechanism of this potential interaction between NEBs and CLCs. Because accumulation of ATP is known for NEB cells, we focused on a possible purinergic signaling pathway. Using ‘sniffer patching’ to detect ATP release, stimulation with high K⁺ was shown to elicit quantal ATP release from NEBs. Use of enhanced ATP hydrolysis and the P2 receptor blocker suramin confirmed that ATP was responsible for activating CLCs following application of high K⁺. A combined pharmacological and Ca²⁺ imaging approach revealed the involvement of functional P2Y₂ receptors, and immunohistochemistry verified the expression of P2Y₂ receptors on CLCs. It is concluded that stimulation of NEBs in ex vivo lung slices evokes exocytosis of ATP and subsequent selective purinergic activation of surrounding CLCs in the NEB microenvironment, which recently has been assigned a potential pulmonary stem cell niche.