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Editorial: More Pieces of the Puzzle in Place, Even More Discovered Missing

Address all correspondence and requests for reprints to: Willis K. Samson, Ph.D., Professor and Chairman, Department of Physiology, University of North Dakota School of Medicine, Grand Forks, North Dakota 58202.

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As early as the 1940s, a role for acetylcholine in the hypothalamic regulation of pituitary function was hypothesized. Pioneering work by Markee, Sawyer, and Everett was extended some years later by Martini’s group in Italy and McCann’s in Texas and it became clear that acteylcholine could regulate GnRH secretion in vivo. Students of neuroendocrinology have followed the subsequent explosion of the literature on the aminergic and peptidergic regulation of GnRH secretory dynamics, but lost in the shuffle to a certain degree was the cholinergic system. Where would the acetylcholine come from that might be a physiologic regulator of peptide release into the median eminence? How is that acetylcholine regulated? What is the mechanism of action? Are the effects physiologically relevant and how does acteylcholine "fit" in the hierarchy of factors that have been demonstrated in vivo and in vitro to affect GnRH secretion? As with all things in neuroendocrinology, solid preliminary observations raise more questions than answers and only once technology advances can the most important aspects of the phenomena already recognized be probed and clarified. In this issue, Catt’s group (1) at NICHD has provided a wealth of novel information that extends significantly those early observations published in Endocrinology almost 50 yr ago (2).

Using cultured hypothalamic cells and the immortalized GnRH-producing GT1–7 cells, Krsmanovic et al. (1) have demonstrated both nicotinic and muscarinic actions of ACh that underlie its biphasic effects on GnRH release. Does this system provide a model for the biphasic effects of other factors on hormone/peptide release? Are the initial stimulatory and subsequent inhibitory effects of other trophic factors not truly dose related, but instead a function of activation (with differing latencies) of multiple ligand receptors on the same or neighboring cells? Could this be the reason for the troublesome, but ever present, bell-shaped dose-response curves that we are loathe to explain to our students?

This manuscript (1) not only characterizes the nicotinic/muscarinic ying/yang effect of ACh but also identifies the intracellular signaling mechanisms recruited, including the remarkable time course of G protein subunit activations. Even within the muscarinic actions, there are both stimulatory (M₁ receptor mediated) and inhibitory (M₂ receptor mediated) effects and those have been linked to unique cellular mechanisms. The report raises several questions, and thus the never ending story seems to continue on, refreshed by these insightful observations. Clearly, both cultured and immortalized cells must express the multiple receptors, but how does the GnRH neuron in its normal, in vivo setting know how (and when) to respond? Are all cholinergic receptors on these cells activated in parallel, or are there some unknown mechanisms by which some receptor subtypes become activated (i.e. up-regulated or sensitized), while others go silent? Even more enticing is the suggestion from the atropine and methoctramine study that these cells themselves produce ACh, which can act in an autocrine fashion to regulate GnRH release, and perhaps even receptor subtype expression. As Catt and colleagues have demonstrated, technology has now advanced to the point where those questions can be addressed. Their group certainly is leading the way. However, the puzzle has many parts and the picture will not be completed until the interactions of the cholinergic system with other aminergic and peptidergic regulators of GnRH have been characterized. Then the most important and difficult questions can be addressed: Why the incredible redundancy (a.k.a. cooperativity) of multiple regulatory factors and how are they coordinated? This work has completed a portion of the puzzle and importantly may have revealed how many more pieces remain missing.

Willis K. Samson, Ph.D.

Professor and Chairman

Department of Physiology

University of North Dakota School of Medicine

Grand Forks, North Dakota 58202

Received August 1, 1998.

	References

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1. Krsmanovic LZ, Mores N, Navarro CE, Abul Saeed S, Arora KK, Catt JK 1998 Muscarinic regulation of intracellular signaling and neurosecretion in GnRH neurons. Endocrinology 139:4037–4043[Abstract/Free Full Text]
2. Everett JW, Sawyer CH, Markee JE 1949 A neurogenic timing factor in the control of the ovulatory discharge of luteinizing hormone in the cyclic rat. Endocrinology 44:234–250[Medline]

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