TABLE 21.
5-HT receptor–interacting proteins and their cellular and physiologic functions
For each receptor, the nature of identified GIPs, their site of interaction, the function of their interaction with the receptor (if known) at the cellular (receptor targeting, trafficking, and signal transduction) and physiologic levels as well as their role in pathologies are indicated. The question marks indicate that the site of interaction of the GIP in the receptor sequence or the physiologic/pathologic functions of its interaction with the receptor remain unknown.
| Receptor | GIP | Site of Interaction | Cellular Functions | Physiologic/Pathologic Functions | References |
|---|---|---|---|---|---|
| 5-HT1A | Calmodulin | i3/Ct | Endocytosis | ? | Della Rocca et al., 1999; Turner et al., 2004, 2007 |
| PKC-dependent receptor phosphorylation | |||||
| Erk1,2 and Jun kinase activation | |||||
| NHE-1 activation | |||||
| Yif1B | Ct | Anterograde trafficking | ? | Al Awabdh et al., 2012; Alterio et al., 2015 | |
| Dendritic targeting | |||||
| 5-HT1B/D | p11 | i3 | ➚Cell surface density and signaling | ➘Depression in rodent models | Svenningsson et al., 2006; Eriksson et al., 2013 |
| ➘Emotional memory in rodents | |||||
| 5-HT2A | β-arrestin 2 | ? | ➚PI3K/Src/Akt signaling | Hallucinogenic effects induced by high 5-HT concentration | Schmid et al., 2008; Bhattacharya et al., 2010; Schmid and Bohn, 2010 |
| Delayed recycling (human receptor) | |||||
| MAP1A | ? | Trafficking in apical dendrites | Allen et al., 2008 | ||
| Arf1-6 | i3/Ct | Coupling to phospholipase D | Robertson et al., 2003 | ||
| Jak/STAT3 | ? | ➚Transcription | Guillet-Deniau et al., 1997 | ||
| RSK2 | i3 | Receptor phosphorylation and desensitization | Putative implication in psychiatric disorders (Coffin-Lowry syndrome) | Sheffler et al., 2006; Allen et al., 2008; Strachan et al., 2009 | |
| 5-HT2A | Calmodulin | i2/Ct | ➘Gq coupling | Turner and Raymond, 2005 | |
| Caveolins | ? | Targeting to lipid rafts Endocytosis | Bhatnagar et al., 2004 | ||
| PSD-95 | Ct (PDZ ligand-SCV) | Dendritic targeting | Hallucinogen effects in mice | Xia et al., 2003; Becamel et al., 2004; Abbas et al., 2009; Pichon et al., 2010; Vogrig et al., 2013; Wattiez et al., 2013 | |
| Postsynaptic localization | Antipsychotic drug effects | ||||
| ➚Phospholipase C | ➘Inflammatory and neuropathic pain | ||||
| ➚Endocytosis | |||||
| Cell surface density | |||||
| SAP97 | Ct (PDZ ligand-SCV) | ➚Gq signaling | ? | Allen et al., 2008 | |
| ➘Endocytosis | |||||
| MUPP1 | Ct (PDZ ligand-SCV) | Postsynaptic localization | Drug dependence | Jones et al., 200; Becamel et al., 2001; Shirley et al., 2004 | |
| ➚Cell surface density | |||||
| MAGI2 | Ct (PDZ ligand-SCV) | Postsynaptic localization | ? | Bécamel et al., 2004 | |
| CIPP | Ct (PDZ ligand-SCV) | Postsynaptic localization | ? | Bécamel et al., 2004 | |
| NHERF3 | ? | ➚Gq signaling | ? | Walther et al., 2015 | |
| ➘Endocytosis | |||||
| 5-HT2B | MUPP1 | Ct (PDZ ligand-SYV/I) | ? | ? | Becamel et al., 2001 |
| PDZ protein | Ct (PDZ ligand-SYV/I) | NO synthesis | ? | Manivet et al., 2000 | |
| 5-HT2C | Calmodulin | Ct | ➚Erk1/2 signaling | ? | Bécamel et al., 2002; Labasque et al., 2008 |
| β-arrestins | i2/? | ➚Erk1/2 signaling | ? | Labasque et al., 2008, 2010; Marion et al., 2004 | |
| Constitutive and agonist-dependent endocytosis | |||||
| MUPP1 | Ct (PDZ ligand-SSV) | ? | ? | Becamel et al., 2001; Parker et al., 2003 | |
| PSD-95 | Ct (PDZ ligand-SSV) | ➚Endocytosis | ? | Bécamel et al., 2002; Gavarini et al., 2006 | |
| ➘Signaling | |||||
| MPP3 | Ct (PDZ ligand-SSV) | ➘Endocytosis | ? | Bécamel et al., 2002; Gavarini et al., 2006 | |
| Veli3/CASK/MintMAGI2, SAP102, PSD93 | Ct (PDZ ligand-SSV) | ? | ? | Bécamel et al., 2002 | |
| 5-HT2C | PICOT | Ct | ? | ? | Bécamel et al., 2002 |
| PTEN | i3 | ? | Rewarding effects of THC and nicotine | Ji et al., 2006 | |
| 5-HT4 | Src | ? | ➚Erk1/2 signaling | ? | Gill et al., 2005; Barthet et al., 2007; Barthet et al., 2009 |
| ➚PLCγ1 | |||||
| p11 | i3 | ➚Cell surface localization | ➘Depression in rodent models | Warner-Schmidt et al., 2009 | |
| ➚Signaling | |||||
| ADAM10 | ? | ➚sAPPα release | ➘β-amyloid plaques | Cochet et al., 2013 | |
| ➘Neuroinflammation | |||||
| GRK5 | Ct | ➘Src activation | ? | Barthet et al., 2009 | |
| ➘Erk1/2 signaling | |||||
| 5-HT4(a) | SNX27a | Ct (PDZ ligand-SCF) | Targeting to endosomes | ? | Joubert et al., 2004 |
| Receptor recycling? | |||||
| NHERF | Ct (PDZ ligand-SCF) | Targeting to microvilli | ? | Joubert et al., 2004 | |
| - interaction with Ezrin | |||||
| CRMP2 | Ct | Neuronal architecture | ? | Joubert et al., 2004 | |
| 5-HT4(b) | PDE3A1, PDE4D3 | ? | Regulation of cAMP signaling | ? | Weninger et al., 2014 |
| 5-HT4(e) | CIPP | Ct (PDZ ligand-VPV) | ? | ? | Joubert et al., 2004 |
| 5-HT4(e) | nNOS | Ct (PDZ ligand-VPV) | ? | ? | Joubert et al., 2004 |
| 5-HT6 | Fyn | Ct (PXHPXR) | ➚Gs signaling | ? | Yun et al., 2007 |
| ➚Erk1/2 signaling | |||||
| ➚Cell surface expression | |||||
| Jab1 | i3/Ct | ➚Gs signaling | ➘Cell death | Yun et al., 2010 | |
| ➚Cell surface expression | |||||
| ➚c-Jun phosphorylation | |||||
| Map1B-LC1 | Ct | ➚Cell surface expression | ? | Kim et al., 2014 | |
| ➘Endocytosis | |||||
| ➚Erk1/2 signaling | |||||
| SNX14 | i3 | ➚Endocytosis | ? | Ha et al., 2015 | |
| ➘Gs signaling | |||||
| mTORC1 | Ct/unknown | ➚mTOR signaling | Cognitive impairment in neurodevelopmental models of schizophrenia | Meffre et al., 2012 | |
| Cdk5, p35 | Ct | Receptor phosphorylation Cdk5 signaling | Neurite growth migration of pyramidal neurons | Duhr et al., 2014; Jacobshagen et al., 2014; Dayer et al., 2015 | |
| 5-HT7 | Neurochondrin | ? | ? | Ward et al., 2009 | |
| Periplakin | ? | ? | Ward et al., 2009 | ||
| S100B | i3 | ➘cAMP | Behavioral despair | Stroth and Svenningsson, 2015 |
PICO, protein kinase C interacting cousin of thioredoxin.