Neuropeptide Y receptors: how to get subtype selectivity

Abstract

The neuropeptide Y (NPY) system is a multireceptor/multiligand system consisting of four receptors in humans (hY(1), hY(2), hY(4), hY(5)) and three agonists (NPY, PYY, PP) that activate these receptors with different potency. The relevance of this system in diseases like obesity or cancer, and the different role that each receptor plays influencing different biological processes makes this system suitable for the design of subtype selectivity studies. In this review we focus on the latest findings within the NPY system, we summarize recent mutagenesis studies, structure activity relationship studies, receptor chimera, and selective ligands focusing also on the binding mode of the native agonists.

Keywords: GPCR; NPY; YR; ligand side; receptor side; subtype selectivity.

FIGURE 1

Important amino acid positions and truncated peptides to introduce selectivity to NPY receptors. (A) Important positions in pNPY (Fuhlendorff et al., 1990; Cabrele et al., 2000, 2002; Parker et al., 2000; Mullins et al., 2001; Soll et al., 2001); (B) Truncations of pNPY (Beck et al., 1989; Fournier et al., 1994; Beck-Sickinger and Jung, 1995; Keire et al., 2000b; Zwanziger et al., 2009). (C) Important positions in hPP (Schwartz, 2006).

FIGURE 2

Peptidic antagonists of the Y₁ receptor (Parker et al., 1998; Koglin et al., 2003).

FIGURE 3

Relevant amino acids in pNPY Ala-scan at NPY receptors. Positions in blue represent the amino acids showing a high impact when exchanged to Ala (Beck-Sickinger et al., 1994).

FIGURE 4

Non-peptidic antagonists for Y₁ and Y₄ receptors. (A) Antagonists for the Y₁ receptor (Rudolf et al., 1994; Hipskind et al., 1997; Wieland et al., 1998; Balasubramaniam et al., 2001; Sjodin et al., 2006; Antal-Zimanyi et al., 2008); (B) Antagonists for the Y₄ receptor (Ziemek et al., 2007).

FIGURE 5

Non-peptidic antagonists of Y₂ and Y₅ receptors. (A) Y₂ receptor antagonists (Doods et al., 1999; Saldanha et al., 2009; Shoblock et al., 2010; Swanson et al., 2011); (B) Y₅ receptor antagonists (Criscione et al., 1998; Kanatani et al., 2000a; Rueeger et al., 2000; Kakui et al., 2006).

FIGURE 6

Binding mode of NPY receptors. (A) hY₁ receptor binding mode (Sautel et al., 1995, 1996; Kannoa et al., 2001; Sjodin et al., 2006; Merten et al., 2007); (B) hY₄ receptor binding mode (Merten et al., 2007); (C) hY₂ receptor binding mode (Merten et al., 2007; Akerberg et al., 2010); (D) hY₅ receptor binding mode (Merten et al., 2007; Lindner et al., 2008b).