History: The human NPY1R cDNA was cloned from a human brain cDNA library. The NPY1R was the first to be characterized, when the expression pattern of an orphan receptor was recognized to overlap with the distribution of NPY in brain. NPY receptors belong to the large superfamily of G-protein-coupled receptors. Many of these receptor genes lack introns, supporting the proposition that they were created via RNA-mediated transpositional events. Differently from the other NPY receptor isoforms NPY1R is the only one containing a single 97-base pairs (bp) intron in the coding region following the fifth transmembrane domain.

A 14-kilobase pair (kb) region of genomic DNA encoding the human neuropeptide Y Y1-receptor gene including 3- and 5- flanking sequences is localized to chromosome 4. It encompasses 8632 bp of DNA (4q32.2) between 164245117 and 164253748 bp. The overall sequence of the gene consists of approximately 10 kb. The genomic structure presents a 6-kb intron situated approximately 150 bp upstream of the start codon within the 5-untranslated region (5UTR), as well as a small intron within the coding region.
The human NPY1R gene is divided into three exons: exon 1 (115 bp), exon 2 (850 bp), and exon 3 (1749 bp). In particular, the NPY1R gene contains three alternative exon 1 sequences (80, 110, and 106 bp) located 6.4, 18.4, and 23.9 kb upstream of exon 2. Exon 1A is located 6.4 kb upstream of exon 2; exon 1B was found a further 12 kb upstream exon 1A, and exon 1C another 5.5 kb upstream of exon 1B. These alternative 5 exons allow the regulation of tissue-specific expression of the receptor. The first 57 nucleotides of the 5UTR of the human NPY1R mRNA are separated by a 6-kb intron from the second exon. The second intron 97 bp, containing an in-frame stop codon, is located at nucleotide 908 in the protein coding region after the fifth transmembrane domain between exon 2 and 3. Moreover, as shown by Nakamura, mouse NPY1R gene contains an alternate exon 4 located over 15 kb downstream of exon 3.

The human cDNA encodes a protein of 384 amino-acids (aa) in lenght that is preceded by approximately 200 bp of 5UTR sequence.

The NPY Y1 receptor subtype (Y1R) was the first to be cloned in the rat, and subsequently in human and mouse. This receptor is as conserved as its ligand (NPY) throughout evolution and mammalian and non-mammalian species. The complete NPY1-36 molecule is necessary for NPY to bind to Y1R. Any proteolytic process leading to alterations in the NH2-terminal domain essentially abolishes the ability of NPY to bind to Y1R. Therefore, NH2-terminally truncated NPY fragments such as NPY2-36, or NPY3-36 have little or no affinity for the Y1R. Modification of COOH-terminal residues does not affect agonist binding. Thus, it has been established that the NH2 terminus is essential for NPY to activate Y1R. The pharmacological profile of the Y1R is characterized by high affinity for NPY, PYY and the corresponding analogs containing Pro³⁴ and low affinity for the N-terminally truncated analogs and for PP.

Y1R has seven putative transmembrane domains associated with G-protein (GPCR). In the N-terminal portion Y1R presents potential sites of glycosylation and in the second extracellular loop, four extracellular cysteines in position 33, 113, 198 and 296 which may form two disulfide bridges (Cys 33 and 296; Cys 133 and 198). Phosphorylation sites are present in the intracellular domain (cysteine in the C-terminal portion at position 338). These cysteines may also explain the capability of palmitate residues to bind to the receptor. As observed for many GPCR, Y1R is internalized together with its ligand into endosomes and recycled to the cell surface within 60 minutes upon agonist stimulation. Moreover, Y1R is able to form homodimers.

The expression of the human NPY Y1 receptor has been studied extensively by using immunohistochemical methods, in situ hybridization experiments and reverse-transcription polymerase chain reaction (RT-PCR; mRNA detection). The human NPY1R is expressed in both central nervous system (i.e., cerebral cortex, thalamus and amigdala) and periphery (i.e., heart, kidneys, gastrointestinal tract, as well as blood vessels).

Nervous system
The NPY Y1R is widely distributed in the central nervous system. A study conducted on four normal human brains revealed that high levels of Y1R receptor mRNA were expressed in cortical areas and in the claustrum, while moderate levels were present in the nucleus accumbens, caudate nucleus, putamen, amygdaloid nuclei and arcuate and paraventricular nuclei of the hypothalamus. Moreover, a study conducted on prefrontal cortex of subjects affected by bipolar disorder, major depression, or schizophrenia revealed a progressive age-related decline in the expression of Y1R mRNA associated with a lack of coexpression with NPY neurons. Interestingly, there was no significant effect of suicide as a cause of death on Y1R mRNA expression levels. In fact, subjects with suicide as a cause of death tended to have higher Y1R mRNA expression levels, but these individuals were among the youngest ones (45 years old) in the population studied.

Periphery
Peripherally, Y1Rs are expressed mainly in arteries and veins, where they are associated with vasoconstriction and potentiation of other vasoconstrictors of neurogenic origin. Although limited, there is evidence of prejunctional Y1R inhibition of neurotransmitter release. Nonetheless, NPY Y1R is primarily located postjunctionally on vascular smooth muscle cells.
1) Colon
In vitro receptor autoradiography ([¹²⁵I]PYY) performed on normal human colonic tissue obtained from nine patients showed that Y1R is distributed only in vessels. No measurable levels of subtype Y1 was identified in smooth muscle, mucosa, muscularis mucosae, as well as in lymphoid follicles, myoenteric and submucosal plexus.
2) Heart
A study conducted on 20-week old fetal human hearts showed that Y1R is present on right ventricular endocardial endothelial cells. In particular, it is highly expressed at the level of the nucleus specifically at the perinucleoplasm and nuclear membrane levels, while lower levels were detected in the cytoplasm and the plasma membrane.
3) Dental pulp
NPY Y1R proteins were present in solubilized membrane preparations of both healthy and inflamed human gingival tissue by Western blotting. Major immunoreactive bands were detected at approximately 55 kDa due to a glycosylated form of the native receptor protein. By using the SwissProt glycosylation prediction packages NetNGlyc and NetOGly, authors confirmed that the human Y1R has potential N- and O-glycosylation sites. The expression of Y1R protein in both healthy and inflamed gingival tissue suggests that NPY could act via the Y1R to exert its tonic effects. Moreover, Y1R was expressed in human dental pulp with evidence of increased expression in carious compared with noncarious teeth. Y1R were localized to nerve fibres and inflammatory cells in the dental pulp of carious teeth.
4) Achilles tendons
Y1R is expressed in the tenocytes in the Achilles tendon. Specifically, Y1R is present within the smooth muscle of the blood vessel walls, but not in the endothelial layer of calcaneal tendons.
5) Skin
In human tissues, RT-PCR and immunocytochemistry studies suggested that Y1R is the primary receptor in human cutaneous circulation, supporting the findings that local non-noradrenergic mechanisms are entirely Y1R-based. Skin blood flow in humans is controlled through two branches of the sympathetic nervous system: a vasoconstrictor system and an active vasodilator system of uncertain neurotransmitter. In this context, NPY showed a vasoconstrictor effect in human subcutaneous arteries that had been dissected out of the abdominal regions from patients who underwent nonvascular disease surgeries (e.g., hernia). NPY decreased cutaneous blood flow via Y1R, with evidence for the additional involvement of postjunctional Y2R. This ability of NPY and Y1R to affect skin vascular conductance varies in accordance with relative innervations at specific sites.

NPY Y1R is a seven transmembrane receptor which has all the characteristics of the GPCR family including potential glycosylation sites in the N-terminal portion and in the second extra-cellular loop.

NPY has been demonstrated to be involved in mitogenic pathways and stimulate cell proliferation via the Y1R. The activation of Y1R is generally associated with reduction of cAMP accumulation, increase of intracellular free calcium concentration ([Ca²⁺]i), and modulation of the MAPK pathway via several signaling molecules, including the protein kinase C (PKC).
Y1R has been involved in several NPY-induced responses, such as activation of neuroendocrine axes, vasoconstriction, anxiolysis, as well as the stimulation of food intake. Moreover, Y1R mediates emotional behavior, stress response, and ethanol consumption.
The prototype of NPY Y1R-mediated responses is vasoconstriction. Specifically, the physiological role of the Y1R subtype was demonstrated in mice lacking Y1R expression, which show no blood pressure response to NPY, but a normal response to norepinephrine. Y1R knockout mice have normal blood pressure, suggesting that the Y1R does not play a crucial role in maintaining blood pressure homeostasis in unstimulated conditions. However, Y1R has been also involved in other NPY-induced responses, such as stimulation of food intake and activation of neuroendocrine axes. In particular, Y1R and Y5R, both expressed in hypothalamic regions involved in the control of feeding, represent the most likely candidates for mediating the appetite stimulatory capacity of NPY. Mice lacking Y1R showed an increased body weight due to a low-energy expenditure rather than high-energy intake. In fact, these mice had a decreased metabolic rate secondary to decreased locomotor activity and movement associated thermogenesis.

The human Y1R subtype shares closest aa identity with the Y4R subtype (42%) and the non-active, human form of the y6 subtype (51%).

In 2004 Ramanathan described a case of autism in which a 19 megabase on chromosome 4q, spanning 4q32 to 4q34, was detected. Being involved in the deletion, those genes which are abundantly expressed in the brain, Y1R and Y5R resulted implicated. In this context, being the neuroproliferative effect of NPY in the hippocampus mediated through the neuropeptide Y Y1R, the authors postulate that the effect of NPY on learning and memory may be mediated through NPY neurogenesis.
Okahisa et al. described that genetic variants of rs7687423 of the NPY1R gene may alter the subjective effects of methamphetamine and result in susceptibility to dependence. Because NPY1R mRNA changes were observed in peripheral tissues and the brain in schizophrenia patients, these findings may also indicate that the NPY1R gene is involved in vulnerability to methamphetamine-induced psychosis because almost all of the analyzed subjects with methamphetamine dependence had comorbid methamphetamine psychosis.