, 1991). In addition, in some motoneurons, AVP can suppress a K+ current (Ogier et al., 2006) that can be barium sensitive (Kolaj and Renaud, 1998). The intracellular

messengers that activate these currents are PKC independent but mediated partially by an AC-cAMP-activated PKA, partially through a yet unknown pathway (Alberi et al., 1997). OTRs can reversibly switch between states of 1–100 nM Kd affinity for agonists and antagonists depending on the presence of divalent cations (Mn2+, Mg2+) and specific interactions with membrane cholesterol. Furthermore, cholesterol also FK228 clinical trial appears required for efficient OTR expression and can stabilize the OTR against thermal or proteolytical degradation. Cholesterol-rich microdomains such as caveolae or lipid rafts can thereby switch a growth-inhibitory effect, induced by OT in an MDCK epithelial kidney cell line, into a proliferative

response, possibly by recruiting a different signaling cascade (Wiegand and Gimpl, 2012). In the rat (though not in the mouse, Insel et al., 1993), OTR expression can be increased by estradiol as well as by withdrawal of progesterone at constant estradiol levels. This occurs in a more region-specific manner, possibly as a result of local progesterone and/or estrogen receptor expression, leading to increased binding in the ventromedial hypothalamus (VMH), the principal nucleus of the bed nucleus of stria terminalis (BST), and medial amygdala, but not in the oval BST and central amygdala (Windle et al., 2006 and references therein). Studies on neuromodulation by OT in these areas should therefore be carefully Selleckchem Protease Inhibitor Library controlled for gender and cycle of the animal. Upon OT activation, OTRs are phosphorylated by G protein-coupled receptor kinase-2,

bind beta-arrestin, and are endocytosed via clathrin-coated vesicles (Smith et al., 2006). After internalization, they recycle back to the plasma membrane via the Rab4/Rab5 short recycling pathway (Conti et al., 2009). This internalization is thought to underlie the rapid desensitization that may occur upon OTR activation. Besides the ability of no various G protein isoforms to activate different pathways, Gi selective ligands generate G protein activation without beta-arrestin recruitment and OTR internalization (Busnelli et al., 2012). Interestingly, whereas endogenous OT can activate OTRs regardless to which G protein they are coupled, specific agonists and antagonists may exhibit differential affinity to OTRs, depending on the specific G protein (Gq, Gi, or Go) to which they are coupled and therefore not cause such internalization. Thus, for example, the OTR agonist atosiban does not promote beta-arrestin1 or beta-arrestin2 recruitment and does not affect receptor internalization, possibly because of a selective activation of only those OTR that are coupled to a Gi protein (Busnelli et al., 2012).