Section 9
Chapter 8,476

Differential sensitivity of the short and long human dopamine D2 receptor subtypes to protein kinase C

Liu, Y.F.; Civelli, O.; Grandy, D.K.; Albert, P.R.

Journal of Neurochemistry 59(6): 2311-2317


ISSN/ISBN: 0022-3042
PMID: 1331329
DOI: 10.1111/j.1471-4159.1992.tb10125.x
Accession: 008475336

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The human dopamine D-2L (long form) and D-2S (short form) receptors were expressed separately in mouse Ltk- fibroblast cells to investigate whether there is a difference in transmembrane signalling of these D-2 receptors. Both receptors induced two signals, a phosphatidylinositol-linked mobilization of intracellular calcium and an inhibition of cyclic adenosine 3'-5' monophosphate (cAMP) accumulation, each with similar response magnitudes and identical pharmacology. Both calcium and cAMP signals were sensitive to pretreatment with pertussis toxin (PTX), indicating mediation by coupling to G-i/G-o proteins. However, the two forms of D-2 receptor were distinguished by acute prior activation of protein kinase C (PKC) with 12-O-tetradecanoyl 4-beta-phorbol 13-acetate (TPA): TPA blocked the D-2S-mediated increase in cytosolic free calcium concentration ((Ca-2+)-i) in a concentration-dependent manner (between 10 nM and 1 mu-M), whereas the D-2L receptor-induced increase in (Ca-2+)-i was resistant to TPA and was only partially (60%) inhibited by 100 mu-M TPA. By contrast, TPA did not alter the inhibition of cAMP accumulation induced by activation of either D-2S or D-2L receptors. We conclude that, in the L cell system, prior activation of PKC differentially modulates the transmembrane signaling of the D-2L and D-2S receptors, preferentially inhibiting the D-2S receptor-mediated calcium signal but not altering the dopamine-induced inhibitory cAMP signal of either receptor subtype.

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