5HT1AR-FGFR1 Heteroreceptor Complexes Differently Modulate GIRK Currents in the Dorsal Hippocampus and the Dorsal Raphe Serotonin Nucleus of Control Rats and of a Genetic Rat Model of Depression

Abstract

The midbrain raphe serotonin (5HT) neurons provide the main ascending serotonergic projection to the forebrain, including hippocampus, which has a role in the pathophysiology of depressive disorder. Serotonin 5HT1A receptor (R) activation at the soma-dendritic level of serotonergic raphe neurons and glutamatergic hippocampal pyramidal neurons leads to a decrease in neuronal firing by activation of G protein-coupled inwardly-rectifying potassium (GIRK) channels. In this raphe-hippocampal serotonin neuron system, the existence of 5HT1AR-FGFR1 heteroreceptor complexes has been proven, but the functional receptor–receptor interactions in the heterocomplexes have only been investigated in CA1 pyramidal neurons of control Sprague Dawley (SD) rats. In the current study, considering the impact of the receptor interplay in developing new antidepressant drugs, the effects of 5HT1AR-FGFR1 complex activation were investigated in hippocampal pyramidal neurons and in midbrain dorsal raphe serotonergic neurons of SD rats and of a genetic rat model of depression (the Flinders Sensitive Line (FSL) rats of SD origin) using an electrophysiological approach. The results showed that in the raphe-hippocampal 5HT system of SD rats, 5HT1AR-FGFR1 heteroreceptor activation by specific agonists reduced the ability of the 5HT1AR protomer to open the GIRK channels through the allosteric inhibitory interplay produced by the activation of the FGFR1 protomer, leading to increased neuronal firing. On the contrary, in FSL rats, FGFR1 agonist-induced inhibitory allosteric action at the 5HT1AR protomer was not able to induce this effect on GIRK channels, except in CA2 neurons where we demonstrated that the functional receptor–receptor interaction is needed for producing the effect on GIRK. In keeping with this evidence, hippocampal plasticity, evaluated as long-term potentiation induction ability in the CA1 field, was impaired by 5HT1AR activation both in SD and in FSL rats, which did not develop after combined 5HT1AR-FGFR1 heterocomplex activation in SD rats. It is therefore proposed that in the genetic FSL model of depression, there is a significant reduction in the allosteric inhibition exerted by the FGFR1 protomer on the 5HT1A protomer-mediated opening of the GIRK channels in the 5HT1AR-FGFR1 heterocomplex located in the raphe-hippocampal serotonin system. This may result in an enhanced inhibition of the dorsal raphe 5HT nerve cell and glutamatergic hippocampal CA1 pyramidal nerve cell firing, which we propose may have a role in depression.

Functional Dimerization of Serotonin Receptors: Role in Health and Depressive Disorders

“…This underscores the possibility that co-activation of protomers may contribute to more effective antidepressant outcomes [203]. These findings provide new insights into the pathogenesis of depressive disorders [204].…”

Membrane Heteroreceptor Complexes as Second-Order Protein Modulators: A Novel Integrative Mechanism through Allosteric Receptor–Receptor Interactions

“…These diverse modifications affect ion channel activities and spatiotemporally regulate membrane potentials and intracellular calcium concentrations. Moreover, the family of G-protein-gated inwardly rectifying potassium channels (Kir3 or GIRK) expressed in the brain, heart, and endocrine tissues were recently shown to stably associate with several different GPCRs, forming the basis of a macromolecular ion channel-GPCR signaling complex [112][113][114]. The molecular determinants that mediate and maintain GPCR-GIRK channel complexes are currently not well understood; however, these protein-protein interaction processes are crucial in determining both the synaptic response times and the extent of GPCR "crosstalk" in GIRK-mediated inhibitory synaptic transmission [113].…”

Understanding electrical and chemical transmission in the brain

“…Also, a D2R–nicotinicR and D3R–nicotinicR hetermeric complexes were found in the striatal DA nerve terminals ( Quarta et al, 2007 ; Bontempi et al, 2017 ). The integration of GPCR and Receptor tyrosine kinases (RTK) in heteroreceptor complexes also has a fundamental role in understanding the mechanism for neuronal plasticity, trophism and modulation of GPCR function ( Borroto-Escuela et al, 2012 , 2013a , b , 2014 , 2015b , 2016a , 2017a , b , 2021 ; Di Liberto et al, 2017 ; Di Palma et al, 2020 ; Ambrogini et al, 2023 ).…”