title: How calmodulin interacts with the adenosine A(2A) and the dopamine D(2) receptors.
abstract: Receptor heteromerization is a mechanism used by G protein-coupled receptors to diversify their properties and function. We previously demonstrated that these interactions occur through salt bridge formation between epitopes of the involved receptors. Recent studies claim that calmodulin (CaM) binds to an Arg-rich epitope located in the amino-terminus of the dopamine D(2) receptor third intracellular loop. This is the same epitope involved in adenosine A(2A)-D(2) receptor heteromerization, through Coulombic interaction between the Arg residues and a phosphorylated serine (pS) located in the medial segment of the C-terminus of the A(2A) receptor. Mass spectrometric analysis indicates that an electrostatic interaction involving the D(2) receptor Arg-rich epitope and several CaM acidic epitopes are mainly responsible for the D(2) receptor-CaM binding. CaM could also form multiple noncovalent complexes by means of electrostatic interactions with an epitope localized in the proximal segment of the C-terminus of the A(2A) receptor. Ca(2+) disrupted the binding of CaM to the D(2) but not to the A(2A) receptor epitope, and CaM disrupted the electrostatic interactions between the D(2) receptor epitope and the more distal A(2A) receptor epitope. A model is introduced with the possible functional implications of A(2A)-D(2)-CaM interactions. These in vitro findings imply a possible regulatory role for CaM in receptor heteromers formation.
authors.affiliation: National Institute on Drug Abuse, IRP, NIH, DHHS, Baltimore, MD 21224, USA. awoods@intra.nida.nih.gov
authors.forename: Amina S
authors.initials: AS
authors.lastname: Woods
authors.forename: Daniel
authors.initials: D
authors.lastname: Marcellino
authors.forename: Shelley N
authors.initials: SN
authors.lastname: Jackson
authors.forename: Rafael
authors.initials: R
authors.lastname: Franco
authors.forename: Sergi
authors.initials: S
authors.lastname: Ferré
authors.forename: Luigi F
authors.initials: LF
authors.lastname: Agnati
authors.forename: Kjell
authors.initials: K
authors.lastname: Fuxe
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002147:Calmodulin / Q000737:chemistry*; D002417:Cattle; D002918:Chymotrypsin / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000032:analysis; D043705:Receptor, Adenosine A2A / Q000737:chemistry*; D017448:Receptors, Dopamine D2 / Q000737:chemistry*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D055672:Static Electricity
chemical_list: D002147:Calmodulin; D010446:Peptide Fragments; D043705:Receptor, Adenosine A2A; D017448:Receptors, Dopamine D2; D002918:Chymotrypsin