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CELLULAR AND MOLECULAR

Coexpression of Y₁, Y₂, and Y₄ Receptors in Smooth Muscle Coupled to Distinct Signaling Pathways

Departments of Physiology and Medicine, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia

Coexpression of Y₁, Y₂, and Y₄ receptors on smooth muscle cells was determined by reverse transcription-polymerase chain reaction, and the receptors were characterized by radioligand binding, selective receptor protection, and functional analysis of signaling pathways. ¹²⁵I-peptide YY (PYY) binding was completely inhibited by neuropeptide Y (NPY) and PYY, and partially inhibited by the Y₁ agonist [Leu³¹, Pro³⁴]NPY or the Y₂ agonist NPY_13–36. In cells where Y₁ receptors were preserved by selective receptor protection, ¹²⁵I-PYY binding was selectively inhibited by the Y₁ agonist or antagonist BIBP 3226 [(R)-N2-(diphenylacetyl)-N-[(4-hydroxyphenyl)methyl]-D-arginine-amide]. Conversely, in cells where Y₂ receptors were preserved, ¹²⁵I-PYY binding was selectively inhibited by the Y₂ agonist or antagonist BIIE 0246 [(S)N²-[1-[2-[4-[(R,S)-5,11-dihydro-6(66H)-oxodibenz[b,e]azepin-11-y]-1piperazinyl]-2-oxoethyl]cyclopentyl]acetyl]-N-[2-[1,2-dihydro-35(4H)-dioxo-1,2-diphenyl-3H-1,2,4-triazol-4-yl]ethyl]-argininamide]. All Y receptors activated preferentially G_i2, but only Y₂ and Y₄ receptors activated G_q. Consequently, Y₂ agonists (NPY, PYY, and NPY_13–36) and the Y₄ agonist (pancreatic polypeptide) induced concentration-dependent contraction, inositol 1,4,5-trisphosphate (IP₃) formation, and increase in cytosolic free Ca²⁺. Contraction induced by Y₂ and Y₄ agonists was not affected by 0 Ca²⁺, Ca²⁺ channel blockers, or pertussis toxin (PTx), but it was abolished by thapsigargin, U73122 [1-(6-(17-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-25-dione], or the myosin light chain kinase inhibitor ML-9 [1-(5-chloronaphthalene-1-sulfonyl)homopiperazine, HCl]. Y₂-mediated contraction was inhibited by the selective Y₂ antagonist BIIE 0246. Insensitivity to PTx implied that the coupling to G_i did not initiate (Y₁) or contribute (Y₂ and Y₄) to contraction. All Y receptor agonists inhibited cAMP formation in a PTx-sensitive manner. The patterns of contraction and inhibition of cAMP by various Y receptors were corroborated by selective receptor protection. The study demonstrates coexpression of Y₁, Y₂, and Y₄ receptors on smooth muscle negatively coupled to adenylyl cyclase via G_i2. Coupling of Y₂ and Y₄ receptors to G_q determines their ability to induce IP₃-dependent Ca²⁺ release and initiate contraction.

Address correspondence to: Dr. John R. Grider, P.O. Box 908711, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VI 23298. E-mail: jgrider{at}hsc.vcu.edu

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