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  • On the other hand there were only


    On the other hand, there were only a few cases that expressed DA2R in our study. Additionally, in the cases whose ACTH-secreting pituitary adenomas expressed DA2R, the ratio of positive staining benzbromarone was very low. This suggests that dopamine agonists may be less effective in canine Cushing's disease than somatostatin analogs. However, it has been reported that dogs with Cushing's disease treated with cabergoline showed therapeutic response in 42.5% of cases; ACTH, α-MSH, and the urinary cortisol-creatinine ratio were significantly decreased. Additionally, the survival times in these cases were longer than the cases treated with ketoconazole (Castillo et al. 2008). In our study, six of 14 cases (43%) expressed DA2R; thus, the expression ratio is approximately the same as that of the therapeutic response ratio in the previous report. This suggests that even if the positive cell ratio is small, therapeutic response might still be expected.
    Conflicts of interest
    Introduction G protein-coupled receptors (GPCRs), with a share of almost 4% of the human genome [1], constitute the largest family of receptors that allow cells to sense extracellular stimuli ∗[2], [3]. These external stimuli range from sensory cues like light, odorants and tastants to small-molecule neurotransmitters, peptides and hormones ∗[2], [3]. This high diversity underscores the fundamental role that GPCRs play in the function of the endocrine, nervous, cardiovascular, sensory and immune systems. The main initial steps of GPCR activation and signaling have been elucidated in detail ∗[2], [4]. These events are initiated by binding of an agonist to a receptor, which triggers a series of conformational changes in the receptor that culminate in its activation. The activated receptor, in turn, binds to and activates heterotrimeric G proteins, which are composed of an α, β and γ subunit and exist in different isoforms. The α and βγ subunits finally modulate the activity of membrane-localized effectors, including ion channels and enzymes like phospholipase Cβ (PLCβ) and adenylyl cyclase. A classic example of the role of these receptors in physiology is their involvement in the regulation of heart contractility. β-adrenergic receptors located on the surface of cardiomyocytes mediate the positive ionotropic and chronotropic effects of adrenalin and noradrenalin, released upon sympathetic activation. Binding of adrenalin or noradrenalin to these receptors, which are coupled to the Gs protein, activate adenylyl cyclases to produce cAMP, which stimulates protein kinase A (PKA). PKA, in turn, phosphorylates different molecules involved in cardiac contractility, including L-type Ca2+ channels, phospholamban and troponin I, ultimately leading to enhanced cardiomyocyte contractility [5]. In addition, cAMP directly promotes the opening of pacemaker (HCN) channels in the conductive tissue, thus increasing heart rate [6], [7]. Parasympathetic activation counteracts these effects via release of acetylcholine, which binds to muscarinic (M2) receptors coupled to Gi/o proteins, thus inhibiting adenylyl cyclase activation. In addition, the βγ subunits released upon Gi/o activation stabilize the membrane potential via activating potassium (GIRK) channels in the conductive tissue [8], [9], [10], [11], [12]. In the endocrine system, GPCRs play an essential role as receptors for several hormones, hypothalamic releasing factors and local modulators. All major known hypothalamic releasing (TRH, GnRH, CRH, GHRH) and inhibiting (somatostatin, dopamine) hormones act via specific GPCRs [13], [14], [15], [16], [17]. With the exception of GH and PRL, anterior (TSH, LH, FSH, ACTH, MSH) and posterior (vasopressin, oxytocin) pituitary hormones also signal through activation of GPCRs [18]. For an extensive discussion of the specific roles of GPCRs and G proteins in human physiology we refer the reader to the comprehensive review by Wettschureck and Offermanns [19].