Purinergic signaling pathways in endocrine system

Abstract

Adenosine-5'-triphosphate is released by neuroendocrine, endocrine, and other cell types and acts as an extracellular agonist for ligand-gated P2X cationic channels and G protein-coupled P2Y receptors in numerous organs and tissues, including the endocrine system. The breakdown of ATP by ectonucleotidases not only terminates its extracellular messenger functions, but also provides a pathway for the generation of two additional agonists: adenosine 5'-diphosphate, acting via some P2Y receptors, and adenosine, a native agonist for G protein-coupled adenosine receptors, also expressed in the endocrine system. This article provides a review of purinergic signaling pathways in the hypothalamic magnocellular neurosecretory cells and neurohypophysis, hypothalamic parvocellular neuroendocrine system, adenohypophysis, and effector glands organized in five axes: hypothalamic-pituitary-gonadal, hypothalamic-pituitary-thyroid, hypothalamic-pituitary-adrenal, hypothalamic-pituitary-growth hormone, and hypothalamic-pituitary-prolactin. We attempted to summarize current knowledge of purinergic receptor subtypes expressed in the endocrine system, including their roles in intracellular signaling, hormone secretion, and other cell functions. We also briefly review the release mechanism for adenosine-5'-triphosphate by neuroendocrine, endocrine and surrounding cells, the enzymes involved in adenosine-5'-triphosphate hydrolysis to adenosine-5'-diphosphate and adenosine, and the relevance of this pathway for sequential activation of receptors and termination of signaling.

Keywords: Adrenal gland; Hypothalamus; Ovary; Pituitary; Testis; Thyroid gland.

Fig. 1

Purinergic signaling pathways. A) The nucleotide-hydrolyzing pathways. The extracellularly released ATP is hydrolyzed to AMP by two enzyme families, E-NPP and E-NTDPase, whereas AMP was efficiently hydrolyzed by E-5NT. Adenosine is further deaminated via inosine into hypoxanthine by ADA and purine nucleoside phosphorylase (PNP), respectively. B, ATP is an agonist for two transmembrane domain P2XRs and several seven transmembrane domain P2YRs, whereas ADP activates a few P2YRs but not P2XRs. Adenosine is also an agonist at four G-protein-coupled ARs. Three subunits in homomeric or heteromeric organization are required for formation of functional P2XRs, whereas dimerization is possible for P2YRs and ARs. Derived from (Stojilkovic, 2009).

Fig. 2

Expression of purinergic receptors in hypothalamo-pituitary unit. Receptors and receptor channels expressed in hypothalamic nuclei (A) and pituitary gland (B). P2XRs and A₂Rs, unidentified subtype(s) of purinergic receptors. For references see the corresponding sections.

Fig. 3

Expression of purinergic receptors in peripheral endocrine glands. For references see the corresponding sections.

Fig. 4

Sequential activation of purinergic receptors in lactotrophs: roles of ectonucleotidases. i) ATP binds to P2X4R, causing an inward sodium/calcium-conducting current, which depolarizes lactotrophs and facilitates firing of action potentials and calcium influx through Ca_v channels. ii) E-NTPDase-mediated generation of ADP from ATP provides a potent agonist for calcium-mobilizing P2Y₁R endogenously expressed in lactotrophs. The released calcium triggers transient cell membrane hyperpolarization by activating calcium-controlled small potassium (SK) channels, accompanied with sustained facilitation of electrical activity through still not well-characterized channel(s). iii) Ecto-5′-nucleotidase-mediated production of adenosine provides an agonist for G_i/o-coupled A₁R, which is also endogenously expressed in these cells. This in turns leads to inhibition of Ca_v channels and facilitation of inwardly rectifying potassium (K_ir) channels and termination of spontaneous and ADP-induced electrical activity. Derived from (Stojilkovic, 2009).