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  • Title: Calcium influx, but not intracellular calcium release, supports PACAP-mediated ERK activation in HEK PAC1 receptor cells.
    Author: May V, Clason TA, Buttolph TR, Girard BM, Parsons RL.
    Journal: J Mol Neurosci; 2014 Nov; 54(3):342-50. PubMed ID: 24723666.
    Abstract:
    In HEK cells expressing GFP-tagged PAC1Hop1 receptors, PACAP augments ERK phosphorylation through two parallel pathways: one through PACAP/PAC1 receptor internalization/endosome MEK/ERK signaling and the other through PLC/DAG/PKC activation. We examined whether elevation of intracellular calcium ([Ca(2+)]i) was required for either of the PACAP/PAC1 receptor-mediated ERK activation mechanisms. The PACAP (25 nM)-induced elevation of [Ca(2+)]i was greater with cells maintained in Ca(2+)-containing than in Ca(2+)-deficient solution, suggesting that both calcium release from internal stores and calcium influx contributed to the rise in [Ca(2+)]i. A thapsigargin-induced increase in [Ca(2+)]i also was greater with calcium in the external solution. OAG, the cell permeable analogue of DAG, increased [Ca(2+)]i, but only in Ca(2+)-containing solution. Decreasing external calcium or depleting internal calcium stores did not block PACAP-induced PAC1 receptor internalization. Omission of calcium from the external solution, but not thapsigargin pretreatment, significantly blunted PACAP-stimulated ERK phosphorylation. The PKC inhibitor BimI decreased PACAP-mediated ERK activation in both Ca(2+)-containing or Ca(2+)-deficient solutions. In contrast, following Pitstop 2 pretreatment to block endocytic mechanisms, PACAP activated ERK only when calcium was present in the external solution. We conclude that the endosome signaling pathway is largely calcium-independent whereas calcium influx appears necessary for the PLC/DAG/PKC component of PACAP-induced ERK activation.
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