LAUSR

Stimulation of transient receptor potential M3 (TRPM3) cation channels with pregnenolone sulfate induces an influx of Ca2+ ions into the cells and a rise in the intracellular Ca2+ concentration, leading to the activation of the activator protein‐1 (AP‐1) transcription factor. Here, we show that expression of a constitutively active mutant of the Ca2+/calmodulin‐dependent protein phosphatase calcineurin attenuated pregnenolone sulfate‐induced AP‐1 activation in TRPM3‐expressing cells. Likewise, expression of the regulatory B subunit of calcineurin reduced AP‐1 activity in the cells following stimulation of TRPM3 channels. MAP kinase phosphatase‐1 has been shown to attenuate TRPM3‐mediated AP‐1 activation. Here, we show that pregnenolone sulfate‐induced stimulation of TRPM3 triggers the phosphorylation and activation of the MAP kinase extracellular signal‐regulated protein kinase (ERK1/2). Pharmacological and genetic experiments revealed that stimulation of ERK1/2 is essential for the activation of AP‐1 in cells expressing stimulated TRPM3 channels. ERK1/2 is required for the activation of the transcription factor c‐Jun, a key component of the AP‐1 transcription factor, and regulates c‐Fos promoter activity. In addition, we identified c‐Jun N‐terminal protein kinase (JNK1/2) as a second signal transducer of activated TRPM3 channels. Together, the data show that calcineurin and the protein kinases ERK1/2 and JNK1/2 are important regulators within the signaling cascade connecting TRPM3 channel stimulation with increased AP‐1‐regulated transcription. J. Cell. Biochem. 118: 2409–2419, 2017. © 2017 Wiley Periodicals, Inc.