Seven Transmembrane-spanning Receptors for Free Fatty Acids as Therapeutic Targets for Diabetes Mellitus: Pharmacological, Phylogenetic, and Drug Discovery Aspects

Costanzi, Stefano; Neumann, Susanne; Gershengorn, Marvin C.

doi:10.1074/jbc.r800014200

Cited by 52 publications

(41 citation statements)

References 39 publications

(50 reference statements)

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“…The members of this family share an overall sequence homology of 30 to 50% and higher within their putative transmembrane domains (Costanzi et al, 2008;Swaminath, 2008). Free fatty acids are not only an integral component of cells, but they also function as signaling molecules.…”

Section: Introductionmentioning

confidence: 99%

Identification and Pharmacological Characterization of Multiple Allosteric Binding Sites on the Free Fatty Acid 1 Receptor

et al. 2012

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Activation of FFA1 (GPR40), a member of G protein-coupling receptor family A, is mediated by medium-and long-chain fatty acids and leads to amplification of glucose-stimulated insulin secretion, suggesting a potential role for free fatty acid 1 (FFA1) as a target for type 2 diabetes. It was assumed previously that there is a single binding site for fatty acids and synthetic FFA1 agonists. However, using members of two chemical series of partial and full agonists that have been identified, radioligand binding interaction studies revealed that the full agonists do not bind to the same site as the partial agonists but exhibit positive heterotropic cooperativity. Analysis of functional data reveals positive functional cooperativity between the full agonists and partial agonists in various functional assays (in vitro and ex vivo) and also in vivo. Furthermore, the endogenous fatty acid docosahexaenoic acid (DHA) shows negative or neutral cooperativity with members of both series of agonists in binding assays but displays positive cooperativity in functional assays. Another synthetic agonist is allosteric with members of both agonist series, but apparently competitive with DHA. Therefore, there appear to be three allosterically linked binding sites on FFA1 with agonists specific for each of these sites. Activation of free fatty acid 1 receptor (FFAR1) by each of these agonists is differentially affected by mutations of two arginine residues, previously found to be important for FFAR1 binding and activation. These ligands with their high potencies and strong positive functional cooperativity with endogenous fatty acids, demonstrated in vitro and in vivo, have the potential to deliver therapeutic benefits.

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Section: Introductionmentioning

confidence: 99%

Identification and Pharmacological Characterization of Multiple Allosteric Binding Sites on the Free Fatty Acid 1 Receptor

et al. 2012

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“…The receptor has been suggested to be a potential target for treatment of type 2 diabetes, as offered by the action of agonists to potentiate glucose-stimulated insulin release (reviewed in Refs. 7,8). Several groups, including ours, have reported the discovery of novel small molecule ligands for FFAR1 (9 -13).…”

mentioning

confidence: 99%

Two Arginine-Glutamate Ionic Locks Near the Extracellular Surface of FFAR1 Gate Receptor Activation

Sum

Tikhonova

Costanzi

et al. 2009

Journal of Biological Chemistry

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Activation of a number of class A G protein-coupled receptors (GPCRs) is thought to involve two molecular switches, a rotamer toggle switch within the transmembrane domain and an ionic lock at the cytoplasmic surface of the receptor; however, the mechanism by which agonist binding changes these molecular interactions is not understood. Importantly, 80% of GPCRs including free fatty acid receptor 1 (FFAR1) lack the complement of amino acid residues implicated in either or both of these two switches; the mechanism of activation of these GPCRs is therefore less clear. By homology modeling, we identified two Glu residues (Glu-145 and Glu-172) in the second extracellular loop of FFAR1 that form putative interactions individually with two transmembrane Arg residues (Arg-183(5.39) and Arg-258(7.35)) to create two ionic locks. Molecular dynamics simulations showed that binding of agonists to FFAR1 leads to breakage of these Glu-Arg interactions. In mutagenesis experiments, breakage of these two putative interactions by substituting Ala for Glu-145 and Glu-172 caused constitutive receptor activation. Our results therefore reveal a molecular switch for receptor activation present on the extracellular surface of FFAR1 that is broken by agonist binding. Similar ionic locks between the transmembrane domains and the extracellular loops may constitute a mechanism common to other class A GPCRs also. G protein-coupled receptors (GPCRs)3 are important components of signal transduction machineries that regulate many physiological processes. They are also important as targets for therapeutic agents; a large percentage of drugs in the marketplace are GPCR ligands or modulators. Knowledge of structurefunction relationships of GPCRs has been gained through many pharmacological, biochemical, and biophysical studies, and has been used extensively to enhance the discovery of GPCR ligands that have been developed into therapeutically useful agents (1-3). Knowledge of the molecular details of ligand-receptor interaction and of the mechanism of receptor activation will also likely improve efforts to identify agonists with better potency and efficacy. Tan et al. (3) have recently reported their design of agonists with higher potency and efficacy for the trace amine receptor 1 based on the rotamer toggle switch model of receptor activation that is thought to operate in a number of class A GPCRs. The rotamer toggle switch typically involves the aromatic residues Trp and Phe within transmembrane helix 6 (TMH6) of GPCRs. During agonist-mediated receptor activation or in constitutively active receptors, the dihedral angle on the side chain of these residues is predicted to be rotated compared with the inactive state and thereby triggers a movement of TMH6 away from TMH3 (e.g. Ref. 4). It is also thought that an ionic lock between an Arg residue in TMH3 and a Glu in TMH6 near the cytoplasmic surface of some GPCRs holds the receptor in the inactive conformation and that receptor activation is accompanied by breakage of the ionic bond when agonist ...

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“…For example, among the FFA family members, FFA1 is activated by medium and long chain (between 6 and 23 carbon) saturated and unsaturated fatty acids [3,4], while both FFA2 and FFA3 respond only to short chain fatty acids (SCFAs) (up to 6 carbon) [5][6][7]. GPR120 responds primarily to long chain (16)(17)(18)(19)(20)(21)(22) carbon) unsaturated fatty acids [8], with a preference sometimes reported for n-3 fatty acids [9], while GPR84 responds to medium chain length (8)(9)(10)(11)(12) carbon) saturated fatty acids [10].…”

Section: Introductionmentioning

confidence: 99%

“…Each of these receptors has generated some interest in drug development programmes, most commonly for the treatment of either metabolic or inflammatory conditions [11][12][13][14][15][16][17]. To date, FFA1 has received the most attention, specifically for the treatment of type 2 diabetes, due to its expression in pancreatic cells and ability to enhance glucosestimulated insulin secretion (GSIS) [4].…”

Section: Introductionmentioning

confidence: 99%

The Therapeutic Potential of Allosteric Ligands for Free Fatty Acid Sensitive GPCRs

Hudson¹,

Ulven²,

Milligan

2013

CTMC

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G protein coupled receptors (GPCRs) are the most historically successful therapeutic targets. Despite this success there are many important aspects of GPCR pharmacology and function that have yet to be exploited to their full therapeutic potential. One in particular that has been gaining attention in recent times is that of GPCR ligands that bind to allosteric sites on the receptor distinct from the orthosteric site of the endogenous ligand. As therapeutics, allosteric ligands possess many theoretical advantages over their orthosteric counterparts, including more complex modes of action, improved safety, more physiologically appropriate responses, better target selectivity, and reduced likelihood of desensitisation and tachyphylaxis. Despite these advantages, the development of allosteric ligands is often difficult from a medicinal chemistry standpoint due to the more complex challenge of identifying allosteric leads and their often flat or confusing SAR. The present review will consider the advantages and challenges associated with allosteric GPCR ligands, and examine how the particular properties of these ligands may be exploited to uncover the therapeutic potential for free fatty acid sensitive GPCRs.

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Seven Transmembrane-spanning Receptors for Free Fatty Acids as Therapeutic Targets for Diabetes Mellitus: Pharmacological, Phylogenetic, and Drug Discovery Aspects

Cited by 52 publications

References 39 publications

Identification and Pharmacological Characterization of Multiple Allosteric Binding Sites on the Free Fatty Acid 1 Receptor

Identification and Pharmacological Characterization of Multiple Allosteric Binding Sites on the Free Fatty Acid 1 Receptor

Two Arginine-Glutamate Ionic Locks Near the Extracellular Surface of FFAR1 Gate Receptor Activation

The Therapeutic Potential of Allosteric Ligands for Free Fatty Acid Sensitive GPCRs

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