Purinergic (P2) Receptor Control of Lower Genitourinary Tract Function and New Avenues for Drug Action: An Overview

Abstract

Micturition, penile erection, contraction of prostatic smooth muscle, peristalsis of the male excurrent duct system and lumbosacral spinal cord neurotransmission all require adenosine 5'-triphosphate (ATP) activity and this likely involves purinergic (P2) receptors. P2 receptors are categorized as either ligand-gated ionotropic P2X or metabotropic G-protein-coupled P2Y subtypes. In the urinary bladder, purinergic receptor mechanisms are involved in both motor and sensory function. In the prostate, P2X1-receptors, which mediate contraction, are present in the fibromuscular stroma while G protein-coupled P2Y purinoceptors have a wide range of actions in prostate cancer. In the excretory ducts of the testis (ductus epididymidis, vas deferens and its associated seminal vesicles), heavy immunostaining for P2X1 and P2X2 subtypes is detected in the membranes of smooth muscle, suggesting their role in sperm transport and ejaculation. In the penis, intense P2X1 and weak P2X2 immunoreactivity are observed in smooth muscle of blood vessels and the corpus cavernosum, implying their participation in detumescence. Human corporal cavernosum stimulation induces relaxation of P2Y purinoceptors. Targeting of extracellular or intracellular P2X and/or P2Y receptor signaling pathways holds promise in affecting the lower genitourinary tract system. Our advancing knowledge about purine agonists and their pharmacologic benefits in erectile, ejaculatory, urinary bladder and prostatic hyperplasia may service clinical problems in the near future.

MicroRNAs May Mediate the Down-Regulation of Neurokinin-1 Receptor in Chronic Bladder Pain Syndrome

“…In contrast to previously published data, 55 we could not reliably detect the expression of P2X3 receptor in either control or patient biopsies, therefore this target was excluded from further analysis. In agreement with the studies showing an increased ATP release in BPS/IC and a concomitant increase in bladder contractility, 56,57 we observed a significant up-regulation of P2Y1 receptor mRNA levels in BPS biopsies. Similarly, there was a strong increase in the levels of muscarinic receptors M3, M4, and M5, and an elevation of M2.…”

Regulation of Smooth Muscle Contraction by the Epithelium: Role of Prostaglandins

“…As depicted in FIGURE 2, ATP, after leaving the nerve ending, directly induces contraction of the smooth muscle cells and at the same time triggers the release of PGE 2 from the epithelial cells, which in turn acts on the smooth muscle cells to trigger the signaling events leading to hyperpolarization and relaxation of the vas deferens. In light of the versatile role of purinergic receptors in control of lower genitourinary tract function, their potential as targets for the development of non-steroidal male contraceptives has been proposed (64). Along this line, our findings have shed new light on the understanding of the detailed mechanism underlying purinergic control of sperm delivery through the vas deferens involving epithelium-derived PGE 2 (155).…”

Purinergic Receptor Expression and Cellular Responses to Purinergic Agonists in Human Prostate Cancer Cells

“…Signaling through purinergic receptors is ubiquitous due to the diversity of purine and pyrimidine ligands, the number of receptors and extracellular nucleotidases. Purinergic signaling has been shown to play a role in many pathways including neurotransmission (2), cell differentiation, hormone secretion, vasodilation, cell proliferation, wound healing and apoptosis (3). There are two distinct families of purinergic receptors: P1 receptors for adenosine and P2 receptors for ATP/ADP and UTP/UDP ligands.…”

“…P2 receptors are further divided into ligand-gated ion channel receptors, P2X, and G protein-coupled receptor, P2Y, subfamilies. To date, four P1 receptors (A 1,2a,2b,3 ), seven P2X receptors (P2X [1][2][3][4][5][6][7] ) and eight P2Y receptors (P2Y 1,2,4,6,11-14 ) have been identified in mammalian cells (4). The adenosine receptor subtypes A 1 and A 3 downregulate the production of cAMP, while A 2a and A 2b subtypes up-regulate the production of cAMP.…”