This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 100/5/703    most recent 01.RES.0000260182.36481.c9v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by McGahon, M. K. Articles by Curtis, T. M. Search for Related Content PubMed PubMed Citation Articles by McGahon, M. K. Articles by Curtis, T. M. Related Collections Animal models of human disease Peripheral vascular disease Type 1 diabetes

(Circulation Research. 2007;100:703.)
© 2007 American Heart Association, Inc.

Cellular Biology

Diabetes Downregulates Large-Conductance Ca²⁺-Activated Potassium ß1 Channel Subunit in Retinal Arteriolar Smooth Muscle

Mary K. McGahon, Durga P. Dash, Aruna Arora, Noreen Wall, Jennine Dawicki, David A. Simpson, C. Norman Scholfield, J. Graham McGeown, Tim M. Curtis

From the Centre for Vision Sciences (M.K.M., D.P.D., A.A., N.W., J.D., D.A.S., T.M.C.), The Queen’s University of Belfast, Institute of Clinical Sciences, Royal Victoria Hospital, Belfast, Northern Ireland; Cell and Metabolic Signalling Group (C.N.S., J.G.M.), School of Medicine and Dentistry, Queen’s University of Belfast, Medical Biology Centre, Belfast, Northern Ireland.

Correspondence to Dr Tim M. Curtis, Centre for Vision Sciences, School of Biomedical Sciences, The Queen’s University of Belfast, Institute of Clinical Sciences, The Royal Victoria Hospital, Grosvenor Road, Belfast BT12 6BA, Northern Ireland. E-mail t.curtis{at}qub.ac.uk

Retinal vasoconstriction and reduced retinal blood flow precede the onset of diabetic retinopathy. The pathophysiological mechanisms that underlie increased retinal arteriolar tone during diabetes remain unclear. Normally, local Ca²⁺ release events (Ca²⁺-sparks), trigger the activation of large-conductance Ca²⁺-activated K⁺(BK)-channels which hyperpolarize and relax vascular smooth muscle cells, thereby causing vasodilatation. In the present study, we examined BK channel function in retinal vascular smooth muscle cells from streptozotocin-induced diabetic rats. The BK channel inhibitor, Penitrem A, constricted nondiabetic retinal arterioles (pressurized to 70mmHg) by 28%. The BK current evoked by caffeine was dramatically reduced in retinal arterioles from diabetic animals even though caffeine-evoked [Ca²⁺]_i release was unaffected. Spontaneous BK currents were smaller in diabetic cells, but the amplitude of Ca²⁺-sparks was larger. The amplitudes of BK currents elicited by depolarizing voltage steps were similar in control and diabetic arterioles and mRNA expression of the pore-forming BK subunit was unchanged. The Ca²⁺-sensitivity of single BK channels from diabetic retinal vascular smooth muscle cells was markedly reduced. The BKß1 subunit confers Ca²⁺-sensitivity to BK channel complexes and both transcript and protein levels for BKß1 were appreciably lower in diabetic retinal arterioles. The mean open times and the sensitivity of BK channels to tamoxifen were decreased in diabetic cells, consistent with a downregulation of BKß1 subunits. The potency of blockade by Pen A was lower for BK channels from diabetic animals. Thus, changes in the molecular composition of BK channels could account for retinal hypoperfusion in early diabetes, an idea having wider implications for the pathogenesis of diabetic hypertension.

Key Words: Ca²⁺ sparks • diabetes mellitus • microcirculation • potassium channels • vascular smooth muscle cells

This article has been cited by other articles:

				L. Borbouse, G. M. Dick, S. Asano, S. B. Bender, U. D. Dincer, G. A. Payne, Z. P. Neeb, I. N. Bratz, M. Sturek, and J. D. Tune Impaired function of coronary BKCa channels in metabolic syndrome Am J Physiol Heart Circ Physiol, November 1, 2009; 297(5): H1629 - H1637. [Abstract] [Full Text] [PDF]

				N. J. Rusch BK channels in cardiovascular disease: a complex story of channel dysregulation Am J Physiol Heart Circ Physiol, November 1, 2009; 297(5): H1580 - H1582. [Full Text] [PDF]

				L. Pang and N. J. Rusch High-conductance, Ca2+-activated K+ Channels: Altered Expression Profiles in Aging and Cardiovascular Disease Mol. Interv., October 1, 2009; 9(5): 230 - 233. [Full Text] [PDF]

				M. K. McGahon, M. A. Needham, C. N. Scholfield, J. G. McGeown, and T. M. Curtis Ca2+-Activated Cl- Current in Retinal Arteriolar Smooth Muscle Invest. Ophthalmol. Vis. Sci., January 1, 2009; 50(1): 364 - 371. [Abstract] [Full Text] [PDF]

				R. Bao, L. M. Lifshitz, R. A. Tuft, K. Bellve, K. E. Fogarty, and R. ZhuGe A Close Association of RyRs with Highly Dense Clusters of Ca2+-activated Cl- Channels Underlies the Activation of STICs by Ca2+ Sparks in Mouse Airway Smooth Muscle J. Gen. Physiol., July 1, 2008; 132(1): 145 - 160. [Abstract] [Full Text] [PDF]