Potassium-selective channels are the largest and most diverse group of ion channels, represented by some 70 known loci in the mammalian genome. The first cloned potassium channel gene was the Drosophila voltage-gated shaker channel, and this was rapidly followed by the identification of other

https://pharmrev.aspetjournals.org/content/pharmrev/57/4/473.full.pdf

International Union of Pharmacology. LIII. Nomenclature and Molecular Relationships of Voltage-Gated Potassium Channels

Although it has been known for many years that estrogen administration has deleterious effects on male fertility, data from transgenic mice deficient in estrogen receptors or aromatase point to an essential physiological role for estrogen in male fertility. This review summarizes the current knowledge on the localization of estrogen receptors and aromatase in the testis in an effort to understand the likely sites of estrogen action. The review also discusses the many studies that have used models employing the administration of estrogenic substances to show that male fertility is responsive to estrogen, thus providing a mechanism by which inappropriate exposure to estrogenic substances may cause adverse effects on spermatogenesis and male fertility. The reproductive phenotypes of mice deficient in estrogen receptors alpha and/or beta and aromatase are also compared to evaluate the physiological role of estrogen in male fertility. The review focuses on the effects of estrogen administration or deprivation, primarily in rodents, on the hypothalamo-pituitary-testis axis, testicular function (including Leydig cell, Sertoli cell, and germ cell development and function), and in the development and function of the efferent ductules and epididymis. The requirement for estrogen in normal male sexual behavior is also reviewed, along with the somewhat limited data on the fertility of men who lack either the capacity to produce or respond to estrogen. This review highlights the ability of exogenous estrogen exposure to perturb spermatogenesis and male fertility, as well as the emerging physiological role of estrogens in male fertility, suggesting that, in this local context, estrogenic substances should also be considered "male hormones."

Estrogen and spermatogenesis.

Functional evidence for the existence of plasma membrane estrogen receptors in a variety of cell types continues to accumulate. Many of these functions originate from rapid signaling events, transduced in response to 17beta-estradiol (E(2)). It has been convincingly shown that E(2) activates phosphoinositol 3-kinase and protein kinase B/AKT, and stimulates ERK and p38 MAP kinases. In part, this stems from G-protein activation and the resulting calcium flux. As a result, the link between E(2) action at the cell membrane and discrete biological actions in the cell has been strengthened. There is now convincing in vitro evidence that E(2) can modulate the functions of neural and vascular cells via non-genomic actions. Thus, the actions of discrete pools of E(2) receptors are likely to contribute to the overall effects of the sex steroids.

Rapid actions of plasma membrane estrogen receptors

Nuclear receptor pharmacology has, to a certain extent, led the way, compared with other receptor systems, in the appreciation that ligands may exert very diverse pharmacology, based on their individual chemical structure and the allosteric changes induced in the receptor/accessory protein complex. This can lead to very selective pharmacological effects, which may not necessarily be predicted from the experience with other agonists/partial agonists/antagonists. If this is the case, then drug discovery may be back to drug-specific pharmacology (where each drug may have an original profile), rather than specific-drug pharmacology (where agents specific for a receptor have a distinct profile). As functional selectivity is indeed a crucial mechanism to be considered when going through the drug discovery development process, then initial screens using reconstituted systems may not show the appropriate pharmacology, simply because the required stoichiometry of corepressors and coactivators may not be present to select the best compounds; therefore, multiple effector systems are necessary to screen for differential activation, and, even then, screening with in vivo pathophysiological models may ultimately be required for the selection process-a massive but necessary task for pharmacologists. Thus, the characterization of nuclear receptors and their associated proteins and the ligands that interact with them will remain a challenge to pharmacologists.

https://pharmrev.aspetjournals.org/content/pharmrev/58/4/685.full.pdf

Overview of Nomenclature of Nuclear Receptors

Increasing evidence has demonstrated striking sex differences in the pathophysiology of and outcome after acute neurological injury. Lesser susceptibility to postischemic and posttraumatic brain injury in females has been observed in experimental models. Additional evidence suggests this sex difference extends to humans as well. The greater neuroprotection afforded to females is likely due to the effects of circulating estrogens and progestins. In fact, exogenous administration of both hormones has been shown to improve outcome after cerebral ischemia and traumatic brain injury in experimental models. The neuroprotection provided by periinjury administration of these hormones extends to males as well. The mechanisms by which estrogen and progesterone provide such neuroprotection are likely multifactorial, and probably depend on the type and severity of injury as well as the type and concentration of hormone present. Both genomic and nongenomic mechanisms may be involved. Estrogen's putative effec...

Gender differences in acute CNS trauma and stroke: neuroprotective effects of estrogen and progesterone.

Maxi-K channels consist of a pore-forming alpha subunit and a regulatory beta subunit, which confers the channel with a higher Ca(2+) sensitivity. Estradiol bound to the beta subunit and activated the Maxi-K channel (hSlo) only when both alpha and beta subunits were present. This activation was independent of the generation of intracellular signals and could be triggered by estradiol conjugated to a membrane-impenetrable carrier protein. This study documents the direct interaction of a hormone with a voltage-gated channel subunit and provides the molecular mechanism for the modulation of vascular smooth muscle Maxi-K channels by estrogens.

https://science.sciencemag.org/content/sci/285/5435/1929.full.pdf

Maria I. Bahamonde

Papers

Acute Activation of Maxi-K Channels (hSlo) by Estradiol Binding to the β Subunit