Vol. 63, No 3/2016 387–396 http://dx.doi.org/10.18388/abp.2016_1366 Review Hypothetical orchestrated cooperation between dopaminergic and kinin receptors for the regulation of common functions* Ibeth Guevara-Lora1*, Anna Niewiarowska-Sendo1, Agnieszka Polit2 and Andrzej Kozik1 1Department of Analytical Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, Kraków, Poland; 2Department of Physical Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, Kraków, Poland The G protein-coupled receptors (GPCRs), one of the tor molecules that form homodimers, heterodimers, or largest protein families, are essential components of high-ordered oligomers can be distinguished (Thomsen the most commonly used signal-transduction systems in et al., 2005; Milligan, 2009; Tadagaki et al., 2012). Dif- cells. These receptors, often using common pathways, ferent types of GPCR assembly have been proposed, may cooperate in the regulation of signal transmission including disulphide bond formation at the N-terminal to the cell nucleus. Recent scientific interests increas- tails, coiled-coil interaction at the C-terminal tails, and ingly focus on the cooperation between these receptors, direct interactions between transmembrane helices (Bou- particularly in a context of their oligomerization, e.g. the vier, 2001). The formation of GPCR oligomers has been formation of dimers that are able to change characteris- widely demonstrated using different techniques, e.g., tic signaling of each receptor. Numerous studies on kinin co-immunoprecipitation, bioluminescent resonance en- and dopamine receptors which belong to this family of ergy transfer, fluorescent resonance energy transfer, and receptors have shown new facts demonstrating their proximity ligation assay (Thomsen et al., 2005). There direct interactions with other GPCRs. In this review, cur- is increasing evidence that the formation of GPCR di- rent knowledge on signaling pathways and oligomeriza- mers/oligomers is associated with a selective regulation tion of these receptors has been summarized. Owing to of physiological processes through changes in signaling the fact that kinin and dopamine receptors are widely pathways (Milligan, 2009). Additionally, the association expressed in cell membranes where they act as media- of the receptors may be helpful during biosynthesis and tors of numerous common physiological processes, the maturation of receptor proteins (Bulenger et al., 2005; information presented here sheds new light on a puta- Dupre & Hebert, 2006). tive crosstalk of these receptors and provides more com- GPCRs possess intracellular loops and C-terminal tails prehensive understanding of possible direct interactions that may bind to several intracellular proteins named that may change their functions. The determination of GPCR-interacting proteins. This group includes hetero- such interactions may be useful for the development of trimeric G proteins (with the α, β and γ subunits), which new targeted therapeutic strategies against many dis- initiate different signaling pathways, depending on the orders in which kinin and dopamine receptors are in- α subunit type (αs, αi, αq, and α12 subtypes). As a con- volved. sequence, several secondary messengers such as cAMP, inositol phosphate, or Ca2+ are generated or, in opposite, Key words: kinin receptors, dopamine receptors, G protein-coupled their production is inhibited. The cellular responses trig- receptors, oligomerization, signaling pathways gered by these messengers include multiple physiological Received: 29 March, 2016; revised: 23 May, 2016; accepted: 06 June, processes such as neurotransmission, cellular metabo- 2016; available on-line: 02 August, 2016 lism, secretion, cellular differentiation, cell growth, and immune responses (Agnati et al., 2003). In recent years, investigations of the interactions between GPCRs and INTRODUCTION *e-mail: [email protected] *This topic was presented in part at the 43rd Winter School of the Kinin and dopamine receptors belong to the class Faculty of Biochemistry, Biophysics and Biotechnology, 16–20 Feb- A (Rhodopsin-like) of the G protein-coupled receptor ruary 2016, Zakopane, Poland. Abbreviations: α R; adrenergic receptor type α ; β R, adrenergic superfamily (GPCRs) responsible for signal transduc- 1B 1B 1 receptor type β ; A R, adenosine receptor type 1; A R, adenosine tion in cells. G protein-coupled receptors have a similar 1 1 2A receptor type 2A; AC, adenylate cyclase; Akt, protein kinase B; AT1R, structure, which includes seven transmembrane domains, angiotensin II receptor type 1; AT2R, angiotensin II receptor type 2; three intracellular loops, three extracellular loops, and C- B1R, bradykinin receptor type 1; B2R, bradykinin receptor type 2; and N-terminal tails. Agonist binding to GPCR is the key cAMP, cyclic adenosine monophosphate; CB1R, cannabinoid recep- tor type 1; D1R, dopamine receptor type 1; D2R, dopamine recep- for the initiation of signal transduction; hence, the recep- tor type 2; D3R, dopamine receptor type 3; D4R, dopamine recep- tor structure plays an important role in the regulation of tor type 4; D5R, dopamine receptor type 5; DAG, diacylglycerol; many physiological cellular functions. Disturbances in ETBR, endothelin receptor type B; Gal1R, galanin receptor type 1; agonist-receptor binding lead to signaling changes that GPCRs, G protein-coupled receptors; GIRK, G protein-gated inward- can trigger pathological processes. An emerging topic of ly rectifying potassium channel; GRKs, G protein-coupled receptor kinases; GSK-3, glycogen synthase kinase 3; 5HT2AR, serotonin 2A research involves cooperation between GPCRs that may receptor; H3R, histamine receptor type 3; IP3, inositol triphosphate; be crucial for the regulation of cell functions (Bouvier, MAPK, mitogen-activated protein kinases; NMDAR, NMDA recep- 2001; Ferre ., 2014). The effectiveness of the agonist tor; NST1R, neurotensin receptor type 1; PI3K, phosphoinositide 3 et al kinase; PKA, protein kinase A; PKC, protein kinase C; PLC, phospho- action on G protein-coupled receptors depends on many lipase C; SST5R, somatostatin receptor type 5; TAAR1, trace amine- factors, among which direct interactions between recep- associated receptor type 1. 388 I. Guevara-Lora and others 2016 β-arrestin have been focused not only on processes re- effective and functional cooperation between kinin and lated to the cellular trafficking machinery of receptors dopamine receptors. but also on the function of β-arrestin as an adaptor mol- ecule that can regulate the receptor signaling (Shenoy DOPAMINE RECEPTORS – CHARACTERISTICS AND & Lefkowitz, 2011). The mechanism of the interactions SIGNALING between β-arrestin and the receptor is biphasic, includ- ing a first phase of loose binding of β-arrestin to the Dopamine, a catecholaminergic neurotransmitter, is an phosphorylated C-terminal tail of GPCR, followed by important modulator of diverse functions of the central the docking of this protein to the receptor core (Ghosh nervous system such as locomotion, cognition, emo- et al., 2015). Hence, interactions with kinases (GRKs) for GPCR phosphorylation are also expected. In fact, such tion, positive reinforcement, food intake, and endocrine regulation (Vallone et al., 2000; Beaulieu & Gainetdinov, interactions lead to increased kinase activity (Maurice et 2005; Hisahara & Shimohama, 2011). This compound al., 2011). It has been suggested that one GRK molecule can successfully phosphorylate both receptors in an oli- also regulates a variety of functions regarding, among gomer complex. Moreover, relevant changes in signaling others, the cardiovascular system, hormone secretion, and the renal and gastrointestinal system (Missale et al., of at least one of the receptors that form this heteromul- 1998). Dopamine acts through specific receptors be- timer can take place after assembling the macromolecu- longing to the GPCRs family. Two groups of dopamine lar complex on cell membranes. The activation of one receptors have been distinguished, both widely distrib- of the participating receptors by its agonist may allosteri- uted in human tissues. The D1-like family comprises the cally suppress or promote the activation of the second receptor types D1 (D1R) and D5 (D5R) and the D2- receptor and may induce conformational changes in the like family contains the receptor types D2, D3, and D4 receptors, leading to the activation of different signaling (D2R, D3R and D4R, respectively) (Missale 1998; pathways (Smith & Milligan, 2010; Ferre et al., 2014). et al., Recently, cooperation of both kinin receptors and do- Vallone et al., 2000). The classification of dopamine re- pamine receptors with other GPCRs, which modulates ceptors is based on their ability to stimulate an intracel- their functions, has been demonstrated. Since these re- lular cAMP increase (D1-type receptors) or to down- ceptors are ubiquitously expressed in many tissues, direct regulate cAMP production due to adenylate cyclase (AC) cooperation between them, which may result in the regu- inhibition (D2-type receptors). lation of crucial cellular processes, seems to be possible. Although dopaminergic receptors possess a similar Therefore, in this review, we present the most recent primary amino acid sequence and a common structure, facts related to protein-protein interaction with concomi- their functions depend mainly on G protein activation tant signaling changes for these two classes