C-type natriuretic peptide (CNP) in the pituitary: is CNP an autocrine regulator of gonadotropes?

Abstract

Natriuretic peptides act via receptors with intrinsic guanylate cyclase activity to stimulate cGMP production and are thought to be important regulators of neuroendocrine systems. C-Type natriuretic peptide (CNP) is of particular interest in this regard because the highest tissue concentrations of CNP occur in the anterior pituitary, where it is a highly potent stimulator of cGMP production. Here we show that pituitaries of rats and mice contain abundant CNP prohormone messenger RNA (mRNA), but no atrial natriuretic peptide or B-type natriuretic peptide prohormone mRNAs. Using reverse transcriptase-polymerase chain reaction, both A- and B-type natriuretic peptide receptor (GC-A and GC-B, respectively) transcripts were detected in rat and mouse pituitaries, although only the GC-B mRNA was measurable by Northern blotting. Immunohistochemistry revealed CNP-positive cells in the anterior, but not posterior, pituitaries of rats, and the vast majority of these cells were identified as gonadotropes by colocalization of CNP and LH immunoreactivities. Targeted toxicity using GnRH conjugated to the ricin-A chain was used to test whether gonadotropes are also direct targets for GnRH action. The conjugate dose dependently inhibited the proliferation of alpha T3-1 cells (gonadotrope-derived cells with GnRH receptors), but had no such effect on GH3 cells (which do not have GnRH receptors). Culture of rat pituitary cells with the conjugate caused comparable reductions in CNP-stimulated cGMP production, GnRH-stimulated LH release, and CA2+ ionophore (A23187)-stimulated LH release, but did not measurably alter cAMP production in response to pituitary adenylate cyclase-activating polypeptide. We conclude that CNP is synthesized in the pituitary, where it is located predominantly in gonadotropes, and GC-B receptors expressed in the pituitary mediate the direct effects of CNP in gonadotropes. Together with the recent demonstration of CNP synthesis and action in alpha T3-1 cells, the data suggest CNP to be a novel autocrine regulator of gonadotropes.

The role of C-type natriuretic peptide in rat testes during spermatogenesis

“…Immunocytochemical analysis demonstrated CNP immunoreactivity localized to gonadotroph cells. 22 Gonadotrophin-releasing hormone neuronal cell lines also express both CNP and NPR-B. 23 These data suggest a paracrine role for CNP in the regulation of gonadotrophinreleasing hormone-secreting hypothalamic neurons and gonadotrophin-releasing hormone-responsive pituitary cells and raise the possibility that CNP may influence the neuroendocrine control of reproduction.…”

Natriuretic peptides: potential modulators of circulatory, renal, respiratory, digestive, endocrine, and central nerve systems and implications of their role in bone remodeling

“…McArdle et al pointed out the effects of the three natriuretic peptides on cGMP production in pituitary cells and showed that CNP is more potent and efficacious than ANP or BNP in the primary culture of rat pituitary cells and in gonadotrope-derived αT3-1 cell line, a clonal gonadotrope-derived cell line (101). The same group also reported that natriuretic peptides stimulate cGMP accumulation in pituitary cells and αT3-1 cells with a rank order of potency (CNP >> BNP > ANP) suggestive of their function via GC-B receptors (102). CNP acts via GC-B receptors to paracrine and/or autocrine effects, and CNP is located in gonadotropes.…”

“…It is reported that ANP and CNP inhibited [ 3 H] isatin binding to rat brain sections and isolated membrane fraction, and isatin antagonized not only NPR-A (ANP-stimulation of GC) but also NPR-C signaling. Competitive interactions between isatin and natriuretic peptides and their receptors give a possible explanation for (99)(100) GC A GC B >> > (101)(102) cGMP (113)(114) hydromineral homeostasis (115)(116)(117)(118) extra follicular cell granulosa cell (127) testosteron synthesis (107)(108) Leydig cell function (106,109) (119)(120)(121) ovary testis adrenal sodium and water homeostasis (105) LH induced progesterone secretion (122,(125)(126) Fig . 3.…”

Critically Ill Patients and Circulating Amino-Terminal Pro-C-Type Natriuretic Peptide

“…In animal models, the regulation of CNP depends on a variety of influencing factors such as glucocorticoids, thyroid hormones, vasoactive peptides, and catabolic state (Igaki et al 1998;Jaszberenyi et al 1998;McArdle et al 1994;Nishimura et al 1998;Prickett et al 2007), but very little is known about regulatory mechanisms in states of critical illness in humans. Using correlation Diet andNutrition in Critical Care DOI 10.1007/978-1-4614-8503-2_24-1 # Springer Science+Business Media New York 2014 analyses, our study revealed significant associations between NT-proCNP and established laboratory biomarkers reflecting inflammation and organ function in medical ICU patients.…”