Cloning of a Human Receptor of the NPY Receptor Family with High Affinity for Pancreatic Polypeptide and Peptide YY

Lundell, Ingrid; Blomqvist, Anders; Berglund, Magnus; Schober, Douglas A.; Johnson, Dwayne; Statnick, Michael A.; Gadski, Robert A.; Gehlert, Donald R.; Larhammar, Dan

doi:10.1074/jbc.270.49.29123

Cited by 304 publications

(181 citation statements)

References 31 publications

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“…Variations within the a helical part of pNPY further revealed an interesting set of CD spectra. [Ala21,Ala25, Pro34]pNPY (24) and cyclo S±S[Cys20,Cys24]pNPY (25) surprisingly showed quite similar CD spectra with the isodichrotic cut of the zero line markedly reduced at 198 nm. In contrast, the three Trp-containing analogues (26±28) maintained an isodichrotic cut of the zero line with pNPY at 203 nm but showed a much higher helicity of up to 64%.…”

Section: Analogues With Replacements At Position 6±8 Of Npymentioning

confidence: 92%

“…[25,26]. A putative Y 3 -receptor has been described only pharmacologically and no specific agonists or antagonists are known [27].…”

mentioning

confidence: 99%

“…Its wide range of action is exerted via several receptor subtypes, named Y 1 -[17±19], Y 2 -[20±22], Y 5 - [23] and y 6 - [24] receptor subtypes, whereas the related peptide PP binds to the Y 4 /PP 1 -receptor [25,26]. A putative Y 3 -receptor has been described only pharmacologically and no specific agonists or antagonists are known [27].…”

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confidence: 99%

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Novel analogues of neuropeptide Y with a preference for the Y₁‐receptor

Söll

Dinger

Lundell

et al. 2001

European Journal of Biochemistry

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In contrast, cyclo S±S [Cys20,Cys24]pNPY was found to be a highly selective ligand at the Y 2 -receptor, binding only threefold less efficiently than NPY. Analogues containing variations of positions 31 and 32 showed highly reduced affinity to the Y 1 -receptor, while binding to the Y 5 -receptor was affected less. Inhibition of cAMP-accumulation of selected peptides with replacements within position 20±23 of NPY showed preserved agonistic properties. The NPY analogues tested give insights into ligand±receptor interaction of NPY at the Y 1 -, Y 2 -and Y 5 -receptor and contribute to our understanding of subtype selectivity. Furthermore, the Y 1 -receptor-preferring peptides are novel tools that will provide insight into the physiological role of the Y 1 -receptor.Keywords: food intake; neuropeptides; NPY; selective ligands; structure±affinity relationship.Obesity, food intake and energy homeostasis are key areas of growing importance because obesity is beginning to replace malnutrition and infectious diseases as the most significant contributor to ill health in the developed world [1]. Neuropeptide Y (NPY) is one of the most important effector molecules of leptin: it is a key molecule in the regulation of food intake, it acts via several different receptor subtypes and elicits several physiological effects. Profound effects on stimulation of food intake, secretion of luteinizing and growth hormone, and insulin release suggest an important role for NPY in the pathophysiology of obesity and diabetes [2±5]. A wide range of other effects of NPY have been reported, such as potent vasoconstriction [6], facilitation of learning and memory [7], modulation of locomotor behaviours [8], induction of hypothermia [9,10], inhibition of sexual behaviour [11], shifts in circadian rhythms [12], modulation of cardiorespiratory parameters[13], anxiolytic potency [14] and inhibition of alcohol consumption and resistance [15].NPY is a 36-amino acid peptide amide belonging to the family of pancreatic polypeptides that includes also pancreatic polypeptide (PP) and peptide YY; it was first isolated from pig brain in 1982 [16].NPY is widely distributed within the central nervous system and in the periphery. [25,26]. A putative Y 3 -receptor has been described only pharmacologically and no specific agonists or antagonists are known [27]. All receptors belong to the G-protein coupled receptor superfamily [28]. The correlation of a certain receptor subtype to a distinct physiological effect is not yet fully understood. Recent studies even suggest that different receptor subtypes redundantly mediate identical actions in a given system, as has been shown for the Y 1 -and Y 5 -receptor in the regulation of food intake [3]. Findings that deficiencies in either the Y 1 -or the Y 5 -receptors do not significantly impair the normal feeding response to fasting or NPY stimulation, strongly indicate that both Y receptors are involved in appetite regulation by NPY [29,30]. Selective receptor agonists or antagonists are useful tools with which to stu...

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Section: Analogues With Replacements At Position 6±8 Of Npymentioning

confidence: 92%

“…[25,26]. A putative Y 3 -receptor has been described only pharmacologically and no specific agonists or antagonists are known [27].…”

mentioning

confidence: 99%

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Novel analogues of neuropeptide Y with a preference for the Y₁‐receptor

Söll

Dinger

Lundell

et al. 2001

European Journal of Biochemistry

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“…All NPY receptors have been shown to mediate their responses through G i/o proteins, which inhibit the accumulation of cAMP (Bard et al, 1995;Gerald et al, 1995Gerald et al, , 1996Herzog et al, 1992;Larhammar et al, 1992;Lundell et al, 1995;Mullins et al, 2000). Several additional intracellular signaling pathways of NPY have been reported in peripheral tissues or cell lines.…”

Section: Introductionmentioning

confidence: 99%

NPY Y1 Receptors Differentially Modulate GABAA and NMDA Receptors via Divergent Signal-Transduction Pathways to Reduce Excitability of Amygdala Neurons

Molosh

Sajdyk

Truitt

et al. 2013

Neuropsychopharmacol

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Neuropeptide Y (NPY) administration into the basolateral amygdala (BLA) decreases anxiety-like behavior, mediated in part through the Y 1 receptor (Y 1 R) isoform. Activation of Y 1 Rs results in G-protein-mediated reduction of cAMP levels, which results in reduced excitability of amygdala projection neurons. Understanding the mechanisms linking decreased cAMP levels to reduced excitability in amygdala neurons is important for identifying novel anxiolytic targets. We studied the intracellular mechanisms of activation of Y 1 Rs on synaptic transmission in the BLA. Activating Y 1 Rs by [Leu 31 ,Pro 34 ]-NPY (L-P NPY) reduced the amplitude of evoked NMDA-mediated excitatory postsynaptic currents (eEPSCs), without affecting AMPA-mediated eEPSCs, but conversely increased the amplitude of GABA A -mediated evoked inhibitory postsynaptic currents (eIPSCs). Both effects were abolished by the Y 1 R antagonist, PD160170. Intracellular GDP-b-S, or pre-treatment with either forskolin or 8Br-cAMP, eliminated the effects of L-P NPY on both NMDA-and GABA A -mediated currents. Thus, both the NMDA and GABA A effects of Y 1 R activation in the BLA are G-protein-mediated and cAMPdependent. Pipette inclusion of protein kinase A (PKA) catalytic subunit blocked the effect of L-P NPY on GABA A -mediated eIPSCs, but not on NMDA-mediated eEPSCs. Conversely, activating the exchange protein activated by cAMP (Epac) with 8CPT-2Me-cAMP blocked the effect of L-P NPY on NMDA-mediated eEPSCs, but not on GABA A -mediated eIPSCs. Thus, NPY regulates amygdala excitability via two signal-transduction events, with reduced PKA activity enhancing GABA A -mediated eIPSCs and Epac deactivation reducing NMDAmediated eEPSCs. This multipathway regulation of NMDA-and GABA A -mediated currents may be important for NPY plasticity and stress resilience in the amygdala.

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“…All investigations agree on the general structure of NPY which is folded in its center forming a hairpin structure with the N-and C-terminal segments in close proximity. The N-terminal polyproline segment (residues 1 -13) is generally disordered and the C-terminal segment (residues 15 -36) is generally helical, [7][8][9][10][11].…”

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confidence: 99%

Solution Structure of Neuropeptide Tyrosine 13–36, a Y2 Receptor Agonist, as Determined by NMR

Labelle

St‐Pierre

Savard

et al. 1997

European Journal of Biochemistry

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The three-dimensional structure of neuropeptide tyrosine (NPY) 13 -36, a specific Y2 receptor agonist, has been investigated by two-dimensional 'H-NMR spectroscopy in solution. Analysis of the doublequantum-filtered correlation spectroscopy (DQFCOSY), total correlation spectroscopy (TOCSY) and nuclear Overhauser enhancement spectroscopy (NOESY) spectra provided a complete assignment of the proton signals. The interproton connectivities observed in the NOESY spectra comprised 166 intraresidue and 95 interresidue distance ranges which were used as constraints for molecular modeling by distance geometry, simulated annealing and energy minimization. The optimal structures are characterized by a helical C-terminal fragment Leu30-Tyr36 and a wide loop from Leu17 to Ser22. The structure of NPY 13-36 is analogous to the structure of NPY under the same solvent conditions. Comparison with other reported Y2 agonists suggests that the helical Leu30-Tyr36 fragment is the most critical for activity.Keywords : neuropeptide tyrosine agonist ; three-dimensional structure; NMR; molecular modeling.Neuropeptide tyrosine or NPY is a 36-amino acid peptide belonging to a family of biologically active peptides which includes peptide YY (PYY) and pancreatic polypeptide (PP). NPY is widely distributed in both the central and peripheral nervous systems and produces a variety of effects especially on the feeding behavior, cardiovascular function and anxiety [ l , 21. Its structure is characterized by the presence of five tyrosine and of four proline residues concentrated in a N-terminal polyproline segment.NPY performs its varied biological functions through the interaction with distinct G-protein-coupled receptor subtypes. Responses to Pro34] The three-dimensional structure of NPY has been investigated by two-dimensional 'H-NMR spectroscopy [12-16) and molecular modeling based on the crystal structure of PP [17-191. All investigations agree on the general structure of NPY which is folded in its center forming a hairpin structure with the N-and C-terminal segments in close proximity. The N-terminal polyproline segment (residues 1 -13) is generally disordered and the C-terminal segment (residues 15 -36) is generally helical, [20-221 and 1,1,1,3,3,3-hexa-fluoro-2-('H2)propano1/20 mM aqueous ('HJacetic acid (3 : 7 at pH 2.7) [23]. Recently, NMR data were reported for NPY 13-36 in ('H,)TFE/water (9 : 1) but the three-dimensional structure could not be determined due to resonance overlap [24]. However, the chemical shift values for the NH and a protons are consistent with helical structure.In this study, the structure of the most common Y2 receptor agonist, NPY 13 -36, has been determined by two-dimensional NMR spectroscopy and molecular modeling. Experiments were performed in deuterated dimethylsulfoxide [(2H,)Me,SO], a solvent of medium polarity which should represent the various media in which the peptide can exist and which is not a helix inducer. These conditions allow us to compare the structure of this fragment with our previously repor...

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Cloning of a Human Receptor of the NPY Receptor Family with High Affinity for Pancreatic Polypeptide and Peptide YY

Cited by 304 publications

References 31 publications

Novel analogues of neuropeptide Y with a preference for the Y₁‐receptor

Novel analogues of neuropeptide Y with a preference for the Y₁‐receptor

NPY Y1 Receptors Differentially Modulate GABAA and NMDA Receptors via Divergent Signal-Transduction Pathways to Reduce Excitability of Amygdala Neurons

Solution Structure of Neuropeptide Tyrosine 13–36, a Y2 Receptor Agonist, as Determined by NMR

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Cloning of a Human Receptor of the NPY Receptor Family with High Affinity for Pancreatic Polypeptide and Peptide YY

Cited by 304 publications

References 31 publications

Novel analogues of neuropeptide Y with a preference for the Y1‐receptor

Novel analogues of neuropeptide Y with a preference for the Y1‐receptor

NPY Y1 Receptors Differentially Modulate GABAA and NMDA Receptors via Divergent Signal-Transduction Pathways to Reduce Excitability of Amygdala Neurons

Solution Structure of Neuropeptide Tyrosine 13–36, a Y2 Receptor Agonist, as Determined by NMR

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Novel analogues of neuropeptide Y with a preference for the Y₁‐receptor

Novel analogues of neuropeptide Y with a preference for the Y₁‐receptor