Nocturnal Accumulation of Cyclic 3′,5′‐guanosine Monophosphate (cGMP) in the Chick Pineal Organ is Dependent on Activation of Guanylyl Cyclase‐B

Abstract

The role of cGMP in the avian pineal is not well understood. Although the light-sensitive secretion of melatonin is a well-known output of the circadian oscillator, pharmacologically elevated cGMP levels do not result in altered melatonin secretory amplitude or phase. This suggests that pineal cGMP signalling does not couple the endogenous circadian oscillator to the expression of melatonin rhythms. Nonetheless, the free-running rhythm of cGMP signalling implies a link to the circadian oscillator in chick pinealocytes. As the circadian rhythm of cGMP levels in vitro is not altered by pharmacological inhibition of phosphodiesterase activity, we infer that the synthesis, rather than the degradation of cGMP, is under circadian control. In vitro experiments with the nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine as well as with an inhibitor of the NO-sensitive soluble guanylyl cyclase (sGC), showed that the NOS-sGC pathway does not play a major role in the circadian control of cGMP generation. In organ culture experiments, we demonstrated that C-type natriuretic peptide (CNP), but not atrial natriuretic peptide (ANP), elevated daytime levels of cGMP. As CNP acts on the membrane guanylyl cyclase isoform B (GC-B), which is expressed at very high levels in mammalian pineals, we investigated the effect of the membrane GC-specific inhibitor HS-142 on chick pineal cGMP levels. CNP-induced daytime cGMP levels were reduced by HS-142. More importantly, 'spontaneously' high nocturnal levels of cGMP in vitro were reduced to daytime levels by acute addition of HS-142. These data implicate endogenous nocturnal CNP release and subsequent activation of GC-B as the major input driving cGMP synthesis in the chick pineal organ.

Molecular Physiology of Membrane Guanylyl Cyclase Receptors

“…However, it is unknown which hormone-GC system drives upstream cGMP production to modulate cGKII activity in the SCN. Because GC-B is the predominant GC expressed in the hypothalamus (238) and CNP has been involved in circadian control of cGMP generation (326), it is tentative to speculate that hypothalamic CNP/GC-B/cGMP/cGKII signaling is involved in the adjustment of the biological clock. Obviously, there are many open questions regarding the potential roles of CNP as neuropeptide.…”

G Protein-Linked Effector and Second Messenger Systems Involved in Melatonin Signal Transduction

“…In contrast to the inhibition of cGMP levels by melatonin noted in a number of systems, the induction of cGMP accumulation by melatonin has been reported in tissues such as lymphocytes [35], chick pineal gland [91], anterior pituitary, thyroid, liver and small intestine [92]. Furthermore, the pigment aggregation induced by melatonin in Xenopus melanocytes can be mimicked by a membrane soluble analogue of cGMP, dibutyryl cGMP [93] and the inhibitory effect of melatonin on melanogen-esis in hamster melanocytes can be mimicked by cGMP [94].…”

“…Although the mechanism of melatonin-induced elevation of cGMP level is undefined, accumulation of cGMP can result from melatonin-induced inhibition of cGMP-PDE activity [83]. Alternatively, activation of GC by melatonin may lead to an elevation of cGMP levels [91]. In the chick pineal gland it is apparent that the cGMP levels rise during the dark phase and have a clear circadian rhythmicity [91], although how the coupling of the circadian clock to cGMP synthesis is relevant to melatonin physiology is not understood and is contradictory to data suggesting an inverse relationship between the levels of melatonin and cGMP.…”

Retinal degeneration protein 3 controls membrane guanylate cyclase activities in brain tissue

“…Expression of CNP and GC-B in different brain regions also indicate a functional role in neuronal tissue. For example, studies investigated a role in synaptic plasticity in the hippocampus ( Decker et al, 2010 ; Barmashenko et al, 2014 ) and an involvement in the regulation of the circadian clock ( Olcese et al, 2002 ). Natriuretic peptides and their receptors have also been identified in the retina ( Rollín et al, 2004 ) and were linked to dopaminergic and cholinergic signaling in amacrine cells ( Abdelalim et al, 2008 ), and to the modulation of GABA-receptor activity in bipolar cells ( Yu et al, 2006 ).…”