Impairment of neurovascular coupling in type 1 diabetes mellitus in rats is linked to PKC modulation of BK_Ca and Kir channels

Abstract

We hypothesized that chronic hyperglycemia has a detrimental effect on neurovascular coupling in the brain and that this may be linked to protein kinase C (PKC)-mediated phosphorylation. Therefore, in a rat model of streptozotocin-induced chronic type 1 diabetes mellitus (T1DM), and in nondiabetic (ND) controls, we monitored pial arteriole diameter changes during sciatic nerve stimulation and topical applications of the large-conductance Ca(2+)-operated K(+) channel (BK(Ca)) opener, NS-1619, or the K(+) inward rectifier (Kir) channel agonist, K(+). In the T1DM vs. ND rats, the dilatory response associated with sciatic nerve stimulation was decreased by ∼30%, whereas pial arteriolar dilations to NS-1619 and K(+) were largely suppressed. These responses were completely restored by the acute topical application of a PKC antagonist, calphostin C. Moreover, the suffusion of a PKC activator, phorbol 12,13-dibutyrate, in ND rats was able to reproduce the vascular reactivity impairments found in T1DM rats. Assay of PKC activity in brain samples from T1DM vs. ND rats revealed a significant gain in activity only in specimens harvested from the pial and superficial glia limitans tissue, but not in bulk cortical gray matter. Altogether, these findings suggest that the T1DM-associated impairment of neurovascular coupling may be mechanistically linked to a readily reversible PKC-mediated depression of BK(Ca) and Kir channel activity.

Neurovascular Regulation in the Ischemic Brain

“…In contrast, impairments in functional hyperemia observed in spontaneously hypertensive rats are not reversed by lowering blood pressure (17), indicating that in contrast to Ang II infusion, the dysfunction occurring in this model may be a result of a chronic structural alteration within the cerebrovasculature. The influence of diabetes on functional hyperemia in the cerebral circulation was recently addressed using rat models of both type I (streptozotocininduced) (77) and type II (Goto-Kakizaki rat) (46) diabetes. Both studies reported impaired cerebral blood flow responses in the somatosensory cortex in response to either the sciatic nerve or whisker stimulation, consistent with an impairment of neurovascular coupling in the diabetic brain.…”

SGK3 Sensitivity of Large-Conductance Ca²⁺-Activated K⁺ Channel

“…In theory, SGK3 could be effective by direct phosphorylation of the channel protein and/or by phosphorylating and thus modifying the activity of other signalling molecules, which in turn influence BK channels. BK channel regulating kinases include AMP activated kinase [107], protein kinase A [108,109], protein kinase C [108,110,111], cGMP-dependent protein kinase (PKG) [112], and cyclindependent kinase isoform CDK5 [113]. BK channels are further regulated by WNK4, which downregulates BK channels, an effect requiring ERK and p38 kinase [89].…”

BKCa channels as physiological regulators: a focused review

“…107 BK Ca channels in astrocytic end feet are believed to mediate the majority of the dilation and the entire vasoconstriction, implicating local extracellular K + as a vasoactive signal for both dilation and constriction. Therefore, BK Ca channels at the astrocytic end foot are able 20 In particular, a significant decrease in the pial arteriolar dilations evoked by somatosensory activation, via sciatic nerve stimulation, was found in streptozotocin-treated diabetic rats. This depressed neurovascular coupling response is likely linked to PKC-mediated changes in BK Ca and K + inward rectifier channel activity, as normal dilating responses of pial arterioles to sciatic nerve stimulation and applications of K + -channel openers were readily restored by acute PKC inhibition.…”

“…However, studies designed to explore the role of BK Ca channels in ischemic 81 and metabolic vasodilation 82 showed no or little effect. Nevertheless, alterations in the activity of BK Ca channels were demonstrated in several vascular pathologies, including diabetes, 20,83,84 atherosclerosis and ischemia, 85 hypertension, 25,51,76 cardiac hypertrophy, 15 and cardiomyopathy.…”