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Differential signaling of dopamine‐D 2 S and ‐D 2 L receptors to inhibit ERK1/2 phosphorylation
Author(s) -
VanHam Irit Itzhaki,
Banihashemi Behzad,
Wilson Ariel M.,
Jacobsen Kirsten X.,
Czesak Margaret,
Albert Paul R.
Publication year - 2007
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2007.04650.x
Subject(s) - receptor , phosphorylation , agonist , biology , protein kinase c , dopamine receptor , signal transduction , kinase , microbiology and biotechnology , chemistry , biochemistry
Although they have distinct functions, the signaling of dopamine‐D 2 receptor short and long isoforms (D 2 S and D 2 L) is virtually identical. We compared inhibitory regulation of extracellular signal‐regulated kinases (ERK1/2) in GH4 pituitary cells separately transfected with these isoforms. Activation of rat or human dopamine‐D 2 S, muscarinic or somatostatin receptors inhibited thyrotropin‐releasing hormone‐induced ERK1/2 phosphorylation, while the D 2 L receptor failed to inhibit this response. In order to address the structural basis for the differential signaling of D 2 S and D 2 L receptors, we examined the D 2 L‐SS mutant, in which a protein kinase C (PKC) pseudosubstrate site that is present in the D 2 L but not D 2 S receptor was converted to a consensus PKC site. In transfected GH4 cells, the D 2 L‐SS mutant inhibited thyrotropin‐releasing hormone‐induced ERK1/2 phosphorylation almost as strongly as the D 2 S receptor. A D 2 S‐triple mutant that eliminates PKC sites involved in D 2 S receptor desensitization also inhibited ERK1/2 activation. Similarly, in striatal cultures, the D 2 ‐selective agonist quinpirole inhibited potassium‐stimulated ERK1/2 phosphorylation, indicating the presence of this pathway in neurons. In conclusion, the D 2 S and D 2 L receptors differ in inhibitory signaling to ERK1/2 due to specific residues in the D 2 L receptor alternatively spliced domain, which may account for differences in their function in vivo .