Phorbol Ester Pretreatment Desensitizes the Inhibition of Ca²⁺ Channels Induced by k‐Opiate, α₂‐Adrenergic, and Muscarinic Receptor Agonists

: Acute treatment of rat spinal cord‐dorsal root ganglion cocultured neurons with 12‐O‐tetradecanoylphorbol 13‐acetate (TPA), a known activator of protein kinase C, inhibited the dihydropyridinc‐sensitive voltage‐dependent ⁴⁵Ca²⁺ influx measured in these cells (IC₅₀ of⋍100 nM, 66% inhibition at 1 νM TPA). However, prolonged preincubation (24 h) of the cells with 100 nM TPA followed by extensive washing completely abolished, i.e., desensitized, the capacity of a second application of TPA to inhibit the activity of the voltage‐dependent Ca²⁺ channels. Moreover, this treatment also abolished the inhibition of Ca²⁺ influx produced by k‐opiate as well as by α₂‐adrenergic and muscarinic receptor agonists. Substantial desensitization was already observed following a 1‐h pretreatment with 100 nMTPA. In contrast to TPA, an inactive phorbol ester (4β‐phorbol 13‐acetate) did not affect the inhibition of the voltage‐dependent Ca²⁺ influx by these receptor agonists. These results suggest that protein kinase C may have a role in the modulation of Ca²⁺channels by k‐opiate, α₂‐adrenetgic, and muscarinic receptor agonists.