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    • Moreover the ubiquitous expression of the OTR and GHSR

    2021-09-13

    Moreover, the ubiquitous desipramine hcl australia of the OTR and GHSR was also observed in hippocampal and hypothalamic primary culture, indicating that this expression pattern is likely due to basal activity of these receptors. GPCR trafficking under control conditions has been linked to biased signalling associated with GPCRs and is known to prolong GPCR signalling (Pavlos and Friedman, 2017). Therefore, the ubiquitous expression of OTR and GHSR may indicate a potential differential or biased signalling at the OTR-GHSR heterocomplex and may have similar consequences for the duration of OTR/GHSR heterocomplex signalling. The ligand-mediated co-trafficking observed between the OTR and GHSR, may also indicate biased signalling of these receptors, due to the significant increased movement of the GHSR into the subcellular region following co-expression and vice versa. Since ligand-mediated biased signalling of the GHSR has recently been documented (Ramirez et al., 2018) it would be interesting to investigate this further. Potentially the most interesting finding is the attenuation of OTR Gαq mediated signalling following OTR/GHSR co-expression and potential heterocomplex formation. The alteration in OTR Gαq signalling may also be influenced by the increased receptor trafficking observed following ligand treatment when the GHSR and OTR are co-expressed in cells. Indeed, the reduction in OTR Gαq signalling may be due to slower recycling of the receptors back to the membrane following formation of the GPCR complex. However, while increased trafficking can be seen with both the OTR and GHSR, no alteration is seen to the GHSR Gαq signalling. Another potential mechanism behind OTR attenuation may include OTR's ability to activate the Gαi signalling pathway (Busnelli and Chini, 2018). The Gαi signalling pathway is known to inhibit production of cAMP and hence activation of PKA (Birnbaumer, 2007), which are both indirect regulators of calcium influx from intracellular stores through co-ordinated crosstalk between the Gαq and Gαi proteins (Borodinsky and Spitzer, 2006; Howe, 2011; Reiken et al., 2003). Therefore, an inhibition of OTR-mediated Gαi activity, may inhibit cAMP and PKA activity, subsequently reducing OTR-mediated calcium influx through the ryanodine receptors, which is the major calcium release channel on the sarcoplasmic reticulum (Reiken et al., 2003). This would further back up the hypothesis that increased receptor trafficking under OTR and GHSR co-expression may induce biased signalling of the OTR and a switch to a Gαi mediated activation and further investigations are warranted. Moreover, we also observed an additional attenuation of OTR-mediated calcium signalling following pre-incubation with GHSR antagonist. A negative binding cooperativity has been shown for heterodimer pairs (Vischer et al., 2011) and thus, it is tempting to speculate that the GHSR has the ability to alter the ligand binding site of the OTR resulting in a reduced affinity of oxytocin for the OTR (El-Asmar et al., 2005). However, further experiments such as radiolabelled binding assays would need to be performed to confirm this hypothesis. Co-expression within the same confocal plane of the OTR/GHSR was also observed in postnatal day 1 rat neuronal cultures of the hippocampus and hypothalamus, highlighting the possibility of the formation of an OTR/GHSR heterocomplex, which is poised to play an important physiological role. The co-localization of OTR and GHSR in the hippocampus and hypothalamus is of particular interest, with reduced OTR signalling within the hippocampus being linked to reduced adult hippocampal neurogenesis (Lin et al., 2017). Neurogenesis is a key factor in memory formation (Deng et al., 2010) and OTR signalling is known to induce long-term spatial memory in the hippocampus (Tomizawa et al., 2003) and to play a role in social discrimination (Raam et al., 2017). Within the hypothalamus, the OTR is known to play a role in food intake, where increased OTR signalling is linked to nutrient excess, notably reduced OTR signalling being linked to the onset of obesity and reduced activity (Blevins and Ho, 2013). Future studies are needed to corroborate central OTR/GHSR heterocomplex formation, such as proximity ligation assays to determine if the functional consequence of heterocomplex formation lead to changes in hippocampal or hypothalamic function.