Potential differences in receptor-mediated G-protein activation in postmortem human hippocampal membranes prepared from healthy controls and suicide victims.

Abstract

Aim: Postmortem brain studies offer enormous opportunities to study molecular mechanisms associated with suicide. In the present study, conventional [³⁵S]GTPγS binding assay and its version-up method ([³⁵S]GTPγS binding/immunoprecipitation assay) were applied to postmortem human hippocampal membranes prepared from suicide victims and control subjects.

Methods: By using conventional [³⁵S]GTPγS binding assay, functional activations of G_i/o proteins coupled with multiple GPCRs (5-HT_1A receptor, α_2A-adrenoceptor, M₂/M₄ mAChRs, adenosine A₁ receptor, histamine H₃ receptor, group II mGlu, GABA_B receptor, μ-opioid receptor, δ-opioid receptor, and NOP receptor) were detected by using 15 different agonists. Furthermore, 5-HT_2A receptor- and M₁ mAChR-mediated Gα_q/11 activation and adenosine A₁ receptor-mediated Gα_i-3 activation were detectable by means of [³⁵S]GTPγS binding/immunoprecipitation assay.

Results: No significant differences in pharmacological parameters of all concentration-response curves investigated were found between suicide victims and control subjects. Significant correlations were obtained for the maximal percent increases between some distinct signaling pathways.

Conclusion: Although only preliminary and auxiliary results were obtained as to the potential differences between suicide victims and control subjects because of the limited number of subjects as well as unmatched age and postmortem delay, adenosine A₁ receptor-mediated Gα_i/o activation and 5-HT_2A receptor-mediated Gα_q/11 activation appear worth focusing on in the future investigations. This study also indicates the possibility that some distinct signaling pathways are interrelated with each other, for example, functional activations of G_i/o proteins coupled to M₂/M₄ mAChR and 5-HT_1A receptor, NOP receptor, and GABA_B receptor, and NOP receptor and δ-opioid receptor.