Published online before print February 9, 2007, doi: 10.1161/01.RES.0000260182.36481.c9
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on August 17, 2006
Revised on January 25, 2007
Accepted on January 29, 2007
Diabetes Downregulates Large-Conductance Ca2+-Activated Potassium 
1 Channel Subunit in Retinal Arteriolar Smooth Muscle
Mary K. McGahon ;
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, The Royal Victoria Hospital, Belfast, Northern Ireland; Cell and Metabolic Signalling Group (C.N.S., J.G.M.), School of Medicine and Dentistry, The Queen’s University of Belfast, Medical Biology Centre, Belfast, Northern Ireland.
* To whom correspondence should be addressed. 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 BK
1 subunit confers Ca2+-sensitivity to BK channel complexes and both transcript and protein levels for BK1 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 BK1 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]
|
|