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

Abstract

Understanding the neurobiological underpinnings of depressive disorder constitutes a pressing challenge in the fields of psychiatry and neurobiology. Depression represents one of the most prevalent forms of mental and behavioral disorders globally. Alterations in dimerization capacity can influence the functional characteristics of serotonin receptors and may constitute a contributing factor to the onset of depressive disorders. The objective of this review is to consolidate the current understanding of interactions within the 5-HT receptor family and between 5-HT receptors and members of other receptor families. Furthermore, it aims to elucidate the role of such complexes in depressive disorders and delineate the mechanisms through which antidepressants exert their effects.

Keywords: 5-HT; 5-HT receptors; depression; receptor dimerization; serotonin.

Figure 1

Scheme of the serotonergic transmission. Serotonin (5-hydroxytryptamine) is synthesized from tryptophan via 5-hydroxytryptophan with the participation of the tryptophan hydroxylase and 5-hydroxytryptophan decarboxylase. The neurotransmitter is packaged into presynaptic vesicles by VMAT and transported to the presynaptic membrane. After releasing into the synaptic cleft, serotonin can interact with 5-HT receptors on the postsynaptic membrane or with 5-HT autoreceptors on the presynaptic membrane. Interaction with autoreceptors is a negative feedback mechanism that prevents further release of serotonin. Serotonin receptors on the postsynaptic membrane include G-protein-coupled receptors and ligand-activated ion channels (5-HT3). Excess serotonin from the synaptic cleft can be uptaken to the presynaptic terminal by the serotonin transporter SERT. At the presynaptic terminal, serotonin can be repackaged into vesicles or deaminated to 5-hydroxyindoleacetic acid by monoamine oxidase. Figure was created with biorender.com.

Figure 2

Signaling pathways activated by 5-HT4Rs and 5-HT7Rs. 5-HT4 and 5-HT7 are Gαs-coupled metabotropic receptors. They activate adenylate cyclase and phospholipase C. Activation of adenylate cyclase leads to the synthesis of an intracellular second messenger—cAMP. cAMP activates protein kinase A as well as cAMP Epac sensors. Protein kinase A and Epac activate ERK kinase, while activation through Epac occurs PKA-independently, through the activation of small GTPases Rap. Activated ERK is able to phosphorylate and thereby activate CREB. CREB is a transcription factor, which induces the expression of a number of neurotrophic proteins, in particular BDNF. Phospholipase C, in turn, cleaves membrane phosphatidylinositol biphosphate to form diacylglycerol and inositol triphosphate. Inositol triphosphate activates protein kinase C, which also leads to activation of ERK kinase. 5-HT4Rs are capable of G-protein independent signaling, namely they are able to directly activate Src tyrosine kinase, which will activate ERK kinase. 5-HT7Rs are capable of signaling through Ga12, which triggers the stimulation of Rho GTPases, Cdc42, and RhoA. These proteins are involved in the regulation of cytoskeletal organization. In addition, 5-HT7Rs modulate the Ca²⁺/calmodulin pathway. Green dots—serotonin or any selective agonist of corresponding receptor. Figure was created with biorender.com.

Figure 3

Homodimerization of serotonin receptors. (A) In the case of the formation of a 5-HT2C homodimer upon inactivation of one of the protomers, a complete blockade of signaling from the homodimer occurs, which leads to the inability of both protomers to activate G-proteins and stimulate the production of inositol triphosphate upon binding to 5-HT. (B) In the 5-HT4 homodimer, each protomer makes an equal contribution to the signal transduction process. Thus, inactivation of one of the protomers leads to a twofold decrease in the efficiency of G-protein activation compared to a homodimer with two intact protomers. (C) Inhibition of one of the protomers 5-HT7 homodimer by risperidone results in the entire dimer becoming inactive for the G-protein. Green dots—serotonin or any selective agonist of corresponding receptor; red dot—antagonist of 5-HT7R risperidone; red crossing—inability to bind ligand/activate G-protein/impossibility of signal transmission. Figure was created with biorender.com.

Figure 4

Heterodimerization between different families and subtypes of serotonin receptors. (A) Heterodimerization of 5-HT1A and 5-HT7 receptors leads to a decrease in the ability of the 5-HT1A receptor to activate the Gi protein, without affecting signal transmission by 5-HT7 receptors. In addition, heterodimerization reduces the ability of the 5-HT1A receptor to activate G-protein-dependent potassium channels, and also enhances the ability of the 5-HT1A receptor to activate MAPKs, particularly ERK. (B) Upon heterodimerization of 5-HT1A and 5-HT2A receptors, activation of the 5-HT2A protomer inhibits the ability of the 5-HT1A protomer to bind ligands. Thus, the 5-HT2A protomer has a dominant effect in the heterodimer. (C) Upon heterodimerization between subtypes of the 5-HT2 receptor family, the 5-HT2C protomer has a dominant effect in the 5-HT2A-5-HT2C and 5-HT2B-5-HT2C heterodimers. Blockade of the 5-HT2C protomer also blocks signal transmission from the 5-HT2A and 5-HT2B protomers. When blocking the 5-HT2A or 5-HT2B protomer, there is no blockade of the 5-HT2C protomer. In the case of the formation of the 5-HT2A-5-HT2B heterodimer, signal transmission from both protomers can be blocked if only one of the 5-HT2A or 5-HT2B protomers is blocked. Green dots—serotonin or any selective agonist of corresponding receptor; red crossing—inability to bind ligand/activate G-protein/impossibility of signal transmission; green checkmark—normal signal transmission. ↑—activation or increase releasing; ↓—inhibition or decrease releasing. Figure was created with biorender.com.

Figure 5

Heterodimerization of 5-HTR with other receptors and proteins. (A) Heterodimerization of D2-5-HT1A in the presence of the antipsychotic clozapine and the HT1A agonist significantly inhibits cAMP production, compared with the effect of this combination of drugs on the receptors separately. In addition, production of IP3 and activation of ERK are noted, which occurs only in the case of the heterodimer. (B) Heterodimerization of the serotonin HT1A receptor and the orexin OX1 receptor increases cAMP production compared with the HT1A receptor that does not form a heterodimer. Heterodimerization of HT1A and OX2 reduces the level of phosphorylation of ERK and CREB. (C) In the 5HT1A-FGFR1 heterodimer, the agonist-activated FGFR1 protomer has an inhibitory effect on the ability of the 5HT1A protomer to open GIRK channels. (D) Heterodimerization of 5-HT2A and the BDNF receptor TrkB suppresses basal autophosphorylation of TrkB and prevents agonist-mediated activation of TrkB without affecting 5-HT2A receptor functions. (E) When melatonin activates the melatonin receptor MT2 in the 5-HT2C-MT2 heterodimer, unidirectional transactivation of the 5-HT2C protomer occurs. (F) 5-HT4-L1 heterodimer exhibits more efficient ERK kinase phosphorylation when stimulated with a 5-HT4 protomer agonist compared to stimulation of the 5-HT4 receptor alone. However, L1 itself does not modulate ERK activation. (G) OXTR-5-HT2A and OXTR-5-HT2C heteroreceptors exhibit bidirectional antagonistic interactions. In this case, the 5-HT2C/5-HT2A protomer is dominant and significantly reduces signal transmission from oxytocin receptors. Lite purple dots—serotonin or any selective agonist of corresponding serotonin receptor; purple dot—clozapine; brown dots—agonists of OX1/OX2 receptors; dark blue dot—agonist of FGFR1; dark green dot—melatonin or any MT2 agonist; orange dot—agonist of OXTR; ↑—activation or increase releasing; ↓—inhibition or decrease releasing. Figure was created with biorender.com.