Abstract
In proestrus, the changing gonadal hormone milieu alters the physiological properties of GnRH neurons and contributes to the development of the GnRH surge. We hypothesized that proestrus also influences the expression of different ion channel genes in mouse GnRH neurons. Therefore, we performed gene expression profiling of GnRH neurons collected from intact, proestrous and metestrous GnRH-GFP transgenic mice, respectively. Proestrus changed the expression of 37 ion channel and 8 calcium homeostasis-regulating genes. Voltage-gated sodium channels responded with upregulation of three alpha subunits (Scn2a1, Scn3a, and Scn9a). Within the voltage-gated potassium channel class, Kcna1, Kcnd3, Kcnh3, and Kcnq2 were upregulated, while others (Kcna4, Kcnc3, Kcnd2, and Kcng1) underwent downregulation. Proestrus also had impact on inwardly rectifying potassium channel subunits manifested in enhanced expression of Kcnj9 and Kcnj10 genes, whereas Kcnj1, Kcnj11, and Kcnj12 subunit genes were downregulated. The two-pore domain potassium channels also showed differential expression with upregulation of Kcnk1 and reduced expression of three subunit genes (Kcnk7, Kcnk12, and Kcnk16). Changes in expression of chloride channels involved both the voltage-gated (Clcn3 and Clcn6) and the intracellular (Clic1) subtypes. Regarding the pore-forming alpha-1 subunits of voltage-gated calcium channels, two (Cacna1b and Cacna1h) were upregulated, while Cacna1g showed downregulation. The ancillary subunits were also differentially regulated (Cacna2d1, Cacna2d2, Cacnb1, Cacnb3, Cacnb4, Cacng5, Cacng6, and Cacng8). In addition, ryanodine receptor 1 (Ryr1) gene was downregulated, while a transient receptor potential cation channel (Trpm3) gene showed enhanced expression. Genes encoding proteins regulating the intracellular calcium homeostasis were also influenced (Calb1, Hpca, Hpcal1, Hpcal4, Cabp7, Cab 39l, and Cib2). The differential expression of genes coding for ion channel proteins in GnRH neurons at late proestrus indicates that the altering hormone milieu contributes to remodeling of different kinds of ion channels of GnRH neurons, which might be a prerequisite of enhanced cellular activity of GnRH neurons and the subsequent surge release of the neurohormone.
Highlights
The hypothalamo-pituitary-gonadal (HPG) neuroendocrine axis has a pivotal role in regulation of reproduction (Knobil, 1988) and maintenance of trophic gonadal hormone supply for different hormone sensitive cellular constituents of the body (Heldring et al, 2007)
We examined the influence of proestrus on the expression of genes encoding various ion channel proteins and regulators of intracellular calcium homeostasis in gonadotropin-releasing hormone (GnRH) neurons dissected from intact, metestrous and proestrous GnRH-GFP transgenic mice brains, respectively
The predicted interactions among proteins encoded by the differentially expressed genes (DEGs) in GnRH neurons of late proestrous mice are depicted in Figures 2, 3, as up- and downregulated clusters, respectively
Summary
The hypothalamo-pituitary-gonadal (HPG) neuroendocrine axis has a pivotal role in regulation of reproduction (Knobil, 1988) and maintenance of trophic gonadal hormone supply for different hormone sensitive cellular constituents of the body (Heldring et al, 2007). At the hypothalamic level of regulation, gonadotropin-releasing hormone (GnRH)-synthesizing neurons are in charge of initiating the reproductive hormone cascade events (Carmel et al, 1976; Merchenthaler et al, 1980). They receive information about the functional performance of the controlled units via hormone feedback mechanisms (Sarkar and Fink, 1980; Herbison, 1998). Disturbances in pulsatile and surge release mechanisms result in anovulatory syndromes and infertility (Henderson et al, 1976; Schally et al, 1976)
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