Diabetes Downregulates Large-Conductance Ca ²⁺ -Activated Potassium β1 Channel Subunit in Retinal Arteriolar Smooth Muscle

Abstract

Abstract-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 Ca 2ϩ release events (Ca 2ϩ -sparks), trigger the activation of large-conductance Ca 2ϩ -activated K ϩ (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 [Ca 2ϩ ] i release was unaffected. Spontaneous BK currents were smaller in diabetic cells, but the amplitude of Ca 2ϩ -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 Ca 2ϩ -sensitivity of single BK channels from diabetic retinal vascular smooth muscle cells was markedly reduced. The BK␤1 subunit confers Ca 2ϩ -sensitivity to BK channel complexes and both transcript and protein levels for BK␤1 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 BK␤1 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. (Circ Res. 2007;100:703-711.)

Functional expression of smooth muscle-specific ion channels in TGF-β1-treated human adipose-derived mesenchymal stem cells

“…Highly expressed BK Ca channels in vascular SMCs regulate arteriolar tone under physiological conditions, and the alteration of BK Ca channels is closely related to vascular diseases such as hypertension, hypertrophy, stroke, atherosclerosis, diabetes, and complications of cardiovascular surgery (14,19,27,38,39). The BK Ca channel is composed of four poreforming ␣-subunits (K Ca 1.1) and ancillary ␤-subunits at a 1:1 ratio (29,58).…”

Microvascular lesions of diabetic retinopathy: clues towards understanding pathogenesis?

“…52 Within the context of diabetic retinopathy, the BK channels on retinal arteriolar VSMCs are particularly important because they show reduced Ca 2 þ sensitivity during early diabetes and render a sustained vasoconstrictive response when compared to non-diabetic controls. 53 BK channel dysfunction during early diabetic retinopathy may represent a central mechanism underlying the hypoperfusion observed in patients and animal models.…”

The Vascular Conducted Response in Cerebral Blood Flow Regulation

“…In hypertensive animals, cerebral artery BK Ca channels are upregulated, 65 whereas in diabetic mice and rats the b 1 -subunit of the BK Ca channel is downregulated, leading to impaired function of the channel. 66,67 Thus, it can be expected that the changes in BK Ca channel expression and function modifies the length constant of VCRs in these diseases. Having defined a key role of K þ channels for modulation of VCRs, it can be predicted that intracellular regulators of K þ channel activity, such as PKC, PKA, 20-HETE, epoxyeicosatrienoic acid (EETs), prostaglandins, and PIP 2 would be capable of regulating VCRs.…”