Dan R. Halm, Ph.D. Associate Professor Address: 149 Biological Sciences II Phone: (937) 775-2742 E-mail: dan.halm@wright.edu Ph.D., University of Iowa, 1981

Research Interests

Epithelial Physiology

Current research interests in my lab focus on the response of intestinal epithelial cells to stimulation from neural and hormonal stimuli. Epithelial tissues form the barrier between the body interior and the external environment; and during digestion, intestinal epithelial cells secrete fluid to promote luminal enzyme action and motility, followed by reabsorption of this fluid to limit water loss from the body. Cells making up the epithelium produce fluid by secreting ions, such as Cl^-, K⁺ and H⁺, into the lumen. Macromolecular secretions amend the composition of this fluid by adding digestive enzymes, mucus, immunoglobulins and other molecules that support the health of the digestive tract. Ion secretory mechanisms involve the action of specific ion transport proteins, such as Na⁺/K⁺-ATPases, Na⁺/K⁺/2Cl^--cotransporters, K⁺ channels and Cl^- channels, which guide flow from the interstitium into the lumen. Regulation of these transport proteins allows for an orderly production of fluid as circumstances change during the day.

Measurement of ion flow is a central activity in the lab, including patch-clamp recording of currents in epithelial cells as well as transepithelial currents. Biochemical assays complement these physiologic measurements by allowing detection of ion channel expression with RT-PCR, immunoblot and immunohistologic methods as well as quantifying changes in signaling molecules of specific regulatory pathways. And, imaging of epithelial structures permits visualization of morphological changes occurring during secretion, with incorporation of fluorescent dyes permitting detection of cellular ion composition (pH, Ca⁺⁺, Cl^-) during the time course of secretory activation. Together these techniques contribute to understanding the normal and pathophysiologic operation of epithelia.

Regulation of ion channels is key to controlling the rate of secretion, and physiologic signals lead both to activation and inhibition. Recent results indicate that sympathetic input activates sustained K⁺ secretion via b₁ and b₂-adrenergic receptors on the epithelial cells in addition to a transient Cl^- secretory event [1, 2]. Divergent intracellular signaling allows these cells to differentially promote the two ion secretory events. Most dramatically, the release of neuropeptide-Y (NPY) by sympathetic nerves leads to a severe blunting of the Cl^- secretory component without altering the rate of sustained K⁺ secretion. Enteroendocrine cells release a related peptide, PYY, such that inhibition of Cl^- secretion can be initiated through two distinct pathways. Both NPY and PYY act via the Y₂-neuropeptide receptor present on epithelial cells, apparently by suppressing cAMP levels. Since both the transient and sustained components of the b-adrenergic response involve cAMP, some type of cytosolic compartmentalization must exist to produce separate cAMP responses, possibly due to phosphodiesterases that limit the spread of cAMP. This regulatory separation allows the epithelial cells to activate groups of ion channels supporting each of the b-adrenergic secretory components. The transient Cl^- secretion requires apical membrane Cl^- channels and basolateral membrane K⁺ channels, whereas sustained K⁺ secretion operates via apical membrane K⁺ channels and basolateral membrane Cl^- channels [5, 7, 8]. Other secretagogs produce higher and more sustained rates of Cl^- secretion, with each secretagog using different types of K⁺ channels to support the secretory events [3, 4]. Clinically, inappropriate regulation of secretion hinders digestion by either restricted or excessive flow. Whereas restricted flow contributes to cystic fibrosis symptoms, excessive fluid secretion contributes to inflammatory bowel disease and irritable bowel syndrome. A greater understanding of secretory regulation will lead to better therapeutic solutions to these and other gastrointestional disorders.

Selected Publications

1. Zhang J, Halm ST, Halm DR. Adrenergic activation of electrogenic K⁺ secretion in guinea pig distal colonic epithelium: desensitization via the Y2-neuropeptide receptor. Am J Physiol Gastrointest Liver Physiol 297:G278-G291, 2009. http://ajpgi.physiology.org/cgi/content/full/00077.2009
2. Zhang J, Halm ST, Halm DR. Adrenergic activation of K⁺ secretion in guinea pig distal colonic epithelium: involvement of b1 and b2 adrenergic receptors. Am J Physiol Gastrointest Liver Physiol 297:G269-G277, 2009. http://ajpgi.physiology.org/cgi/content/full/00076.2009
3. Halm ST, Liao T, Halm DR. Distinct K⁺ conductive pathways are required for Cl^- and K⁺ secretion across distal colonic epithelium. Am J Physiol Cell Physiol 291:C636-C648, 2006. http://ajpcell.physiology.org/cgi/reprint/291/4/C636
4. Liao T, Wang L, Halm ST, Lu L, Fyffe REW, Halm DR. The K⁺ channel K_VLQT (Kcnq1) located in the basolateral membrane of distal colonic epithelium is not essential for activating Cl^- secretion. Am J Physiol Cell Physiol 289:C564-C575, 2005. http://ajpcell.physiology.org/cgi/reprint/289/3/C564
5. Halm DR. Secretory control of basolateral membrane potassium and chloride channels in colonic crypt cells. Cell Volume and Signaling, edited by Lauf PK, Adragna NC. New York: Springer, 2004, p. 119-129. http://ebooks.ohiolink.edu/xtf-ebc/view?docId=tei/sv/0387237526/0387237526.xml;chunk.id=ch11;toc.depth=1;toc.id=part3;brand=default
6. Michail SK, Halm DR, Abernathy F. Enteropathogenic Escherichia coli: Stimulating neutrophil migration across a cultured intestinal epithelium without altering transepithelial conductance. J Ped Gastroenterol Nutr 36:253-260, 2003. http://journals.lww.com/jpgn/pages/articleviewer.aspx?year=2003&issue=02000&article=00018&type=abstract
7. Li Y, Halm ST, Halm DR. Secretory activation of basolateral membrane Cl^- channels in guinea pig distal colonic crypts. Am J Physiol Cell Physiol 284:C918-C933, 2003. http://ajpcell.physiology.org/cgi/reprint/284/4/C918
8. Li Y, Halm DR. Secretory modulation of basolateral membrane inwardly rectified K⁺ channel in guinea pig distal colonic crypts. Am J Physiol Cell Physiol 282:C719-C735, 2002. http://ajpcell.physiology.org/cgi/reprint/282/4/C719
9. Halm DR, Halm ST. Prostanoids stimulate K⁺ secretion and Cl^- secretion in guinea pig distal colon via distinct pathways. Am J Physiol Gastrointest Liver Physiol 281:G984-G996, 2001. http://ajpgi.physiology.org/cgi/reprint/281/4/G984
10. Halm DR, Halm ST. Secretagogue response of goblet cells and columnar cells in human colonic crypts. Am J Physiol Cell Physiol 277:C501-C522, 1999 (Corrigenda 278:C212-C233, 2000). http://ajpcell.physiology.org/cgi/reprint/278/1/C212
11. Halm DR. Identifying swelling-activated channels from ion selectivity patterns. J Gen Physiol 112:369-371, 1998. http://jgp.rupress.org/cgi/content/full/112/3/369
12. Rechkemmer G, Frizzell RA, Halm DR. Active K⁺ transport across guinea pig distal colon: action of secretagogues. J Physiol 493:485-502, 1996. http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1158932&blobtype=pdf
13. Halm DR, Halm ST. Aldosterone stimulates K⁺ secretion prior to onset of Na⁺ absorption in guinea pig distal colon. Am. J. Physiol., Cell Physiol. 266:C552-C558, 1994. http://ajpcell.physiology.org/cgi/reprint/266/2/C552