Despite their undisputed importance however FPR

Despite their undisputed importance, however, FPR receptors are not in the limelight of GPCR-related research (for review [12] and references therein). We, therefore, draw attention to this GPCR receptor family, in order to re-initiate FPR-related research, particularly in the light of biased agonism (for review [[13], [14], [15]] and references therein).
Biased agonism Formyl peptide receptors are activated by a surprisingly high number of structurally and chemically unrelated ligands, which elicit different cellular responses, that are specific to ligand and cell type [[42], [43], [44]]. For example, the endogenous protein AnxA1 (annexin A1) and its N-terminal peptide Ac2-26 exhibit anti-inflammatory reactions, whereas bacterially-derived fMLP promotes pro-inflammatory signal transduction [45]. SAA (Serum Amyloid A) enhances DNA binding of transcription factors NF-κB and activator protein 1 (AP-1) via hFPR2 interactions, leading to increased transcription and subsequent release of inflammatory cytokines; whereas LXA4 interactions with hFPR2 transduce anti-inflammatory, i.e., pro-resolving signals, via the inhibition of the same pathways. In addition, LXA4 triggers the expression of metalloproteinase-2, which is not activated by SAA/hFPR2 interactions [46]. These observations, however, are difficult to grasp with the classical concept of receptor biochemistry, which classifies ligand/receptor interactions only in terms of agonists and antagonists [47] (). Ligands were considered to be agonists when they cause activation, and antagonists, in turn, are ligands that inhibit the activation exerted by agonists. This model implied that there are only two distinguishable states: an active occupied by agonists and an off-state, which is inactive and stabilized by an antagonist. This “classical” view on receptor Medroxyprogesterone synthesis suggests that only the receptor itself is responsible for the kind (i.e., the quality) of the elicited downstream signal, and ligands, on the other hand, determine its intensity (i.e., the quantity). Hence, signal transduction pathways and the affected intracellular second messenger systems would always the same, only the level of activation is a function of and dictated by the actual ligand/receptor interaction. However, as described in this chapter, FPR2/ligand interactions reveal entirely different cellular responses, a finding, which ultimately questions the “classical” theory of receptor/ligand interaction. Biased agonism (Fig. 2) allows to incorporate these findings into a solid concept (for review [13,14,48,49] and references therein) and offers an elegant explanation as to why different FPR2 agonists do not cause the same effects. Biased agonism describes the ability of a ligand to selectively activate subsets of downstream signaling pathways coupled to a receptor while inhibiting others. GPCRs, or receptors in general, populate multiple conformations (for review [13,14] and references therein). Each of these is capable to preferentially interact with all or maybe specific (sub)sets of intracellular signal transducers. The interaction of agonists with their corresponding receptors shifts this conformational equilibrium towards defined, i.e., ligand-selected conformers and ultimately defines the repertoire of cellular responses elicited by a specific receptor/ligand interaction. Essentially, this process determines the available receptor signaling and in turn, the signal path that is linked to a specific GPCR/ligand interaction (for review [13,14,48,49] and references therein).
FPR ligands Because human FPRs are expressed on immune cells and mediate key events during inflammation, drugs targeting of these receptors is mainly useful for the treatment of inflammatory diseases. We surmise that similar to drug development for GPCRs, in general, the development of biased ligands acting on FPRs is a promising therapeutic approach to stimulate the desired responses while - at the same time – avoiding or even reducing adverse effects (for review [[13], [14], [15]] and references therein).