Flip-Flopping Retinal in Microbial Rhodopsins as a Template for a Farnesyl/Prenyl Flip-Flop Model in Eukaryote GPCRs

Abstract

Thirty years after the first description and modeling of G protein coupled receptors (GPCRs), information about their mode of action is still limited. One of the questions that is hard to answer is: how do the allosteric changes in the GPCR induced by, e.g., ligand binding in the end activate a G protein-dependent intracellular pathway (e.g., via the cAMP or the phosphatidylinositol signal pathways). Another question relates to the role of prenylation of G proteins. Today’s “consensus model” states that protein prenylation is required for the assembly of GPCR-G protein complexes. Although it is well-known that protein prenylation is the covalent addition of a farnesyl- or geranylgeranyl moiety to the C terminus of specific proteins, e.g., α or γ G protein, the reason for this strong covalent binding remains enigmatic. The arguments for a fundamental role for prenylation of G proteins other than just being a hydrophobic linker, are gradually accumulating. We uncovered a dilemma that at first glance may be considered physiologically irrelevant, however, it may cause a true change in paradigm. The consensus model suggests that the only functional role of prenylation is to link the G protein to the receptor. Does the isoprenoid nature of the prenyl group and its exact site of attachment somehow matter? Or, are there valid arguments favoring the alternative possibility that a key role of the G protein is to guide the covalently attached prenyl group to – and it hold it in – a very specific location in between specific helices of the receptor? Our model says that the farnesyl/prenyl group – aided by its covalent attachment to a G protein -might function in GPCRs as a horseshoe-shaped flexible (and perhaps flip-flopping) hydrophobic valve for restricting (though not fully inhibiting) the untimely passage of Ca 2+ , like retinal does for the passage of H + in microbial rhodopsins that are ancestral to many GPCRs.

Intraluminal Farnesol and Farnesal in the Mealworm's Alimentary Canal: An Unusual Storage Site Uncovering Hidden Eukaryote Ca2+-Homeostasis-Dependent “Golgicrine” Activities

“…In addition to the cited emerging questions, this paper also tries to answer the still only partially answered question on how endogenous sesquiterpenoids act at the molecular level. Is it only at the level of transcription (29,31) and/or on the whole integrated system of Ca 2+ -homeostasis (1,28,69)?…”

“…Van Mellaert et al (73) reported on the anti-JH effect of some synthetic benzoylphenols that caused sterility in female insects (inhibition of ovarian development) without being mutagenic like other types of chemosterilants are. In signaling systems in which farnesol acts through prenylation (28), just adding farnesol to the diet may not suffice in conditions where the enzymes needed for prenylation are absent. All-trans farnesol (also named farnesol EE) is commercially available in large quantities at reasonable prices.…”

“…The molecular weight (MW) of farnesol is 222.3 g/mol. Its rotatable bond count is 7, indicating that it is a very flexible molecule (1,28). The best documented isomers of farnesol are: trans, trans-farnesol, 2-cis,6-trans-farnesol, 2-trans,6-cis-farnesol and cis-cis-farnesol (see PubChem), the all trans isomer being the most active in the Tenebrio JH-bioassay (25).…”

“…No specific vertebrate-type bioassay for farnesol is known, this in sharp contrast with the situation in insects where farnesol, and even more its juvenile hormone esters, are known to be master hormone systems in controlling development (see next). It is neither well-known that farnesol plays a role in GPCR signaling through its role in prenylation of G-proteins (28). Prenylation is important, e.g., for RAS protein functioning from yeast to humans (41).…”

Alzheimer’s Disease: Is a Dysfunctional Mevalonate Biosynthetic Pathway the Master-Inducer of Deleterious Changes in Cell Physiology?

“…It takes a horseshoe shape ( Figure 1C). These properties are probably important for its function in prenylation, a key phenomenon in the functioning of G protein Coupled Receptors (GPCRs) and in binding to receptor-pockets in helixbundle transmembrane proteins [11]. Defective prenylation may play a role in Alzheimer's disease.…”