bindingaffinity
Bluelighter
- Joined
- Apr 19, 2012
- Messages
- 150
Common knowledge has it that the recreational effects of GHB, GBL, and 1,4-BD are due to their effects on a non-GABA GHB receptor. (C.f. the differences in effects between the non-recreational, non-convulsant selective GABA-B agonist baclofen and GHB and its analogues, which are both recreational and lower seizure threshold.)
However, reading the literature, it seems very unclear what this receptor actually is, even though many papers casually refer to it as if its something that's been solidly identified.
The one identification that I'm aware of is a highly cited paper, Cloning and functional characterization of a gamma-hydroxybutyrate receptor identified in the human brain by Christian Andriamampandry, Omar Taleb, V?ronique Kemmel, Jean-Paul Humbert, Dominique Aunis, and Michel Maitre (The FASEB Journal 2007 21:3, 885-895). This paper identifies the GHB receptor with GPR 172A.
A 2010 paper, Identification and Comparative Functional Characterization of a New Human Riboflavin Transporter hRFT3 Expressed in the Brain, by Yoshiaki Yao, Atsushi Yonezawa, Hiroki Yoshimatsu, Satohiro Masuda, Toshiya Katsura and Ken-ichi Inui (J Nutr. 2010 Jul;140(7):1220-6) identified GPR 172A as a riboflavin transporter, denoted hRFT3. The identification of this gene as a riboflavin transporter (later named SLC52A2) seems pretty well accepted by the genetics community, with OMIM giving all 3 names (GPR 172A, SLC52A2, and RFT3) to the gene. HUGO also identifies it as GPR 172A, SCL52A2, and RFT3, and notably not anything GHB related. Same for UniProt. Even IUPHAR identifies it only as a riboflavin transporter. (IUPHAR's only activity listed for GHB as a ligand is at a hydroxycarboxylic acid receptor predominantly expressed in adipose tissue and the pituitary gland, whose primary endogenous ligand is lactic acid and whose primary exogenous ligand is niacin.)
There are two attempts to resolve this dilemma that I've seen. One of them is a 2013 article, γ-Hydroxybutyric Acid (GHB) Is Not an Agonist of Extrasynaptic GABAA Receptors by Connelly, William M., Adam C. Errington, and Vincenzo Crunelli (PLoS ONE 8.11 (2013): e79062). Another is this Stack Exchange question, which openly asks the same thing I'm asking: is the GHB receptor equivalent to RFT3? Given what we know about GHB pharmacology, this seems wildly unlikely to me.
Furthermore, although human genetics is complicated, I would expect a disorder of the GHB receptor to bear some relationship to SSADH (a disorder which causes high levels of GHB due to inability to metabolize it), either showing similar or opposite symptoms. (See 22q11.2 microdeletion and microduplication, or Williams syndrome and its reciprocal microduplication, for examples of what I mean by "opposite".) SSADH symptoms largely seem like a logical consequence of persistent high levels of GHB intoxication throughout early development, whereas the one known disorder of RFT3, Brown-Vialetto-Van Laere syndrome, does not seem related in a meaningful way to what we know about GHB pharmacology. (Fun fact: the SSADH page is the only mention throughout all of OMIM for GHB, unless they've updated since I compiled the resources for this post.)
So, what the hell is going on here?
Did Andriamampandry's paper identify the wrong receptor?
Note: I don't have institutional access to journals, so it's quite possible that there's relevant research I missed because I couldn't get access to it, or because my library skills atrophied.
However, reading the literature, it seems very unclear what this receptor actually is, even though many papers casually refer to it as if its something that's been solidly identified.
The one identification that I'm aware of is a highly cited paper, Cloning and functional characterization of a gamma-hydroxybutyrate receptor identified in the human brain by Christian Andriamampandry, Omar Taleb, V?ronique Kemmel, Jean-Paul Humbert, Dominique Aunis, and Michel Maitre (The FASEB Journal 2007 21:3, 885-895). This paper identifies the GHB receptor with GPR 172A.
A 2010 paper, Identification and Comparative Functional Characterization of a New Human Riboflavin Transporter hRFT3 Expressed in the Brain, by Yoshiaki Yao, Atsushi Yonezawa, Hiroki Yoshimatsu, Satohiro Masuda, Toshiya Katsura and Ken-ichi Inui (J Nutr. 2010 Jul;140(7):1220-6) identified GPR 172A as a riboflavin transporter, denoted hRFT3. The identification of this gene as a riboflavin transporter (later named SLC52A2) seems pretty well accepted by the genetics community, with OMIM giving all 3 names (GPR 172A, SLC52A2, and RFT3) to the gene. HUGO also identifies it as GPR 172A, SCL52A2, and RFT3, and notably not anything GHB related. Same for UniProt. Even IUPHAR identifies it only as a riboflavin transporter. (IUPHAR's only activity listed for GHB as a ligand is at a hydroxycarboxylic acid receptor predominantly expressed in adipose tissue and the pituitary gland, whose primary endogenous ligand is lactic acid and whose primary exogenous ligand is niacin.)
There are two attempts to resolve this dilemma that I've seen. One of them is a 2013 article, γ-Hydroxybutyric Acid (GHB) Is Not an Agonist of Extrasynaptic GABAA Receptors by Connelly, William M., Adam C. Errington, and Vincenzo Crunelli (PLoS ONE 8.11 (2013): e79062). Another is this Stack Exchange question, which openly asks the same thing I'm asking: is the GHB receptor equivalent to RFT3? Given what we know about GHB pharmacology, this seems wildly unlikely to me.
Furthermore, although human genetics is complicated, I would expect a disorder of the GHB receptor to bear some relationship to SSADH (a disorder which causes high levels of GHB due to inability to metabolize it), either showing similar or opposite symptoms. (See 22q11.2 microdeletion and microduplication, or Williams syndrome and its reciprocal microduplication, for examples of what I mean by "opposite".) SSADH symptoms largely seem like a logical consequence of persistent high levels of GHB intoxication throughout early development, whereas the one known disorder of RFT3, Brown-Vialetto-Van Laere syndrome, does not seem related in a meaningful way to what we know about GHB pharmacology. (Fun fact: the SSADH page is the only mention throughout all of OMIM for GHB, unless they've updated since I compiled the resources for this post.)
So, what the hell is going on here?
Did Andriamampandry's paper identify the wrong receptor?
Note: I don't have institutional access to journals, so it's quite possible that there's relevant research I missed because I couldn't get access to it, or because my library skills atrophied.