My Research Page

Hi, here I am sitting in Rockford lonely, so don't forget to send e-mail to me at jackc@uic.edu. Most of this page is blah, blah, blah for read-write professor types. If you are like most web people and like visual stuff then click on the links to slide presentations. You can click below for any slide (although I recommend the uninitiated go in sequence.) To view the slide presentations you will have to be in the IE browser. You will see buttons to the right or below every slide which let you go forward or back. Good luck. Send me an e-mail if you have a problem.

How the Peptide Oxytocin Increases Female Sexual Behavior

My study of behavioral neuroendocrinology has led me to delve into questions of how steroids like estradiol and progesterone interact with peptides such as oxytocin to change how, why and when we have sex. We have found that the peptide oxytocin (OT) increases female sexual receptivity. We also feel that this is due to its ability to keep animals together in social and reproductive situations. Click here to see the slides. So it appears that OT enhances female sexual behavior by making the stimuli from the male less aversive than it would be otherwise. Which stimuli is not known, although they certainly respond to mounting with a lot of fighting unless OT is there. For more on this see the next section.

Immediate Effects of Steroids on Oxytocin Release

So how can steroids like estradiol affect OT levels other than by affecting OT synthesis? Click here to see one possible way. This shows that estradiol releases oxytocin from brain sites about as fast as we can get it out of our superfusion apparatus, demonstrating that estradiol affects this release of oxytocin without acting on its synthesis, which is how most people thought it had its effects. We have what we think are unique ideas about how steroids interact with G-proteins at these new binding sites and how these sites interact with each other. We have a paper the submitted version of which you can view by clicking here, that was published in J. of Neuroendocrinology in 1989 that explains this unique idea. You will need Acrobat Reader to read this.

How do Steroids have these rapid effects on cellular functions?

So we are back to the idea that steroids have actions at the membrane level. We have found something startingly new about these receptors which is published in Hormones and Metabolic Research (Caldwell, J. D. Evidence of Sex Hormone Binding Globulin Binding Sites in the Medial Preoptic Area and Hypothalamus. Hormones & Metabolic Research 33:7-9, 2001). It turns out that these binding sites may be receptors for a large protein called sex hormone binding globulin (SHBG), which was formerly thought to be a carrier protein for steroids in blood. To see a slide show on these binding sites and data showing that SHBG has behavioral effects and receptors in brain click here. To see a pdf version of our manuscript that was just published in Brain Research 874:24-29, showing that SHBG facilitates female sexual receptivity click here. You will need Acrobat Reader to read this.

What is Sex Hormone Binding Globulin doing in the Brain?

Gee, it's March 2006 and I just read that stuff above and it's pretty out of date.

First, with the help of my good friend and co-Editor Gustav Jirikowski, I have been Guest Editor on a volume of Hormones and Metabolic Research to appear in April of 2006 entitled “Emerging Roles for Steroid Binding Globulins”. Here is an eflyer for that volume with a list of articles. We begin that volume with an article examining data that several binding globulins have an active role in mediating steroid actions. For example, there is membrane-associated receptor for retinol binding globulin, which is critical for uptake of retinol (vitamin A) into cells. Similarly for vitamin D there is a membrane-associated called megalin (sounds like something that would attack Tokyo). Dr. Thomas Andreassen, who writes a fine review in our volume, is part of a laboratory that demonstrated in Cell last September that SHBG is internalized in association with megalin. We are now examining whether SHBG is internalized in brain (see below). Other articles include one by Herbert et al. showing that oxytocin and SHBG are found in the same synaptic vesicles in the posterior pituitary and median eminence. Sendemir and colleagues also show the changes in SHBG, which increases near parturition, across pregnancy, parturition and lactation. Schock et al. find SHBG’s brother binding globulin androgen binding protein (ABP; they share the same gene) in the human heart, where its expression is correlated with testosterone levels. There is another binding globulin that has turned up in brain, it is corticosteroid binding globulin (CBG). Mopert and colleagues found that CBG is also co-localized with both oxytocin and vasopressin in the paraventricular and supraoptic nuclei in the rat hypothalamus. The distribution of CBG is similar to that of SHBG, except it is found in the suprachiasmatic nucleus whereas SHBG is only found dorsal to the SCN. Sivukhina and colleagues then demonstrate a similar distribution for CBG in the human brain. So check this volume out!

Here is some more SHBG identification discovered by Dr. Jirikowski and an excellent researcher, Dr. Zsofia Herbert, at the University of Jena we have found out a lot about SHBG in the brain. To see a slide presentation about these findings click here. If you would rather read, we have found that SHBG is made in the same brain areas as oxytocin (click here to see a composite of photos and here to see a map of this co-localization published in Brain Research in 2003) and that it is in fact found in the same synaptic vesicles as oxytocin, in varicosities suggesting that it is released within the brain. This is perhaps why it has behavioral effects similar to oxytocin. Further, we have found SHBG in Herring bodies of the posterior pituitary, sometimes co-localized with oxytocin. In a paper published in Neuroendocrinology (click here to have a pdf version of the pre-print) we examined SHBG production with RT-PCR, we found that there was a lot of SHBG in brains of ovariectomized rats receiving sesame oil vehicle, but that treating such animals with estradiol virtually eliminated SHBG expression. (click here to see the representative [no really] bands of the RT-PCR). This suggests that SHBG in brain may be very important when steroid levels are low, but that, like other steroid-binding proteins like the estradiol receptors, estradiol exerts negative feedback effects on SHBG expression. Zsofia did mass spectrometry (SELDI-TOF; I can barely pronounce it) on brain SHBG and found that it has the same constituents as peripheral SHBG (click here to see these SELDI spectra, they're cool), suggesting that it is capable of binding steroids. Gustav has also found that SHBG is co-localized in neurons that contain estradiol receptor a (ERa) and ERb (click here to see SHBG-ERbeta colocalization) indicating that either SHBG is internalized by cells containing ERs (possibly suggesting an important interaction of the two estradiol-binding proteins) or they are produced in the same cells. Wait for the in situ hybridization studies to answer which. Therefore, it looks like SHBG is made in brain, particularly under conditions where steroid levels are low, is then released into brain and the pituitary, it binds to steroids and then may affect post-synaptic receptors. I have drawn all of this together in a grand scheme in a paper that has been accepted for publication in Neuroscience and Biobehavioral Reviews (to see a pdf version this paper click here), discussing interactions between oxytocin and SHBG receptors (and P-BSA and E-BSA binding sites) related to control of sexual arousability.

Most recently we have been examining two rapid effects of SHBG in brain. First, we have found that SHBG is internalized by brain cells. We have discovered this by infusing SHBG coupled to a fluor into the brain. First, we see uptake of SHBG in the ependyma of the cerebroventricles (click here to see a picture), then it appears in cells surrounding blood vessels (see here) which may be Hortega cells. Finally, we have seen fluorescence in cells in the lateral and caudal PVN and the SON (see here). We have also seen examples of uptake of the same fluor coupled to SHBG into HT22 hippocampal cells that Dr. Robert Shapiro of Oregon Health Sciences Center has stably transfected with cDNA for ERa (click here). Our most extensive examination of the dynamics of SHBG uptake has been done using ¹²⁵I-labeled SHBG, which is specifically taken up into the same HT22 cells with either ERa or ERb cDNA as well as in some surprising cells such as the fibroblast cell line 3T3, the neuroblastoma cell line C6 and the adrenal medullary cell line PC-12. We also have evidence that SHBG stimulates some of these cell lines very rapidly to phosphorylate their MAP kinase. This would suggest that not only is there a very rapid effect of SHBG on these cells but it affects a system that is important for the neuroprotective effects of estradiol (see the fine work of our friends Dan Dorsa and Bob Shapiro, who sent us the HT22 cells). We are pursuing the relationship of SHBG uptake and receptors to known effects of steroids.

Dr. Funmilayo Suleman in my laboratory is also working hard to identify the protein that is the receptor for SHBG in brain. She has found that hypothalamic homogenates are capable of binding SHBG if they are from estradiol-treated rats (click here) but not from ovariectomized rats not receiving estradiol. She has also isolated bands from similar homogenates of hypothalamus that bind to SHBG on a purification column and result in bands of 70 and ~160 kDa on western blots (click here). We are trying hard to examine the protein nature of these bands, but, as Forest Gump said, “That’s all I can say about that.” So look at the volume and stay tuned.

Here are two beautiful women and outstanding scientists. On the left is Dr. Funmilayo Suleman, excellent molecular biologist and mother of three. On the right is Student Dr. Cordula Seeber from Gustav’s lab at Friedrich Schiller University in Jena Germany, who did some of her thesis work on the response of brain CBG to stress in my lab.

Click here to go back to the main page.

This page created September 28, 1999

Revised April 3, 2006