Potassium channels and neurovascular coupling

Abstract

Neuronal activity is communicated to the cerebral vasculature so that adequate perfusion of brain tissue is maintained at all levels of neuronal metabolism. An increase in neuronal activity is accompanied by vasodilation and an increase in local cerebral blood flow. This process, known as neurovascular coupling (NVC) or functional hyperemia, is essential for cerebral homeostasis and survival. Neuronal activity is encoded in astrocytic Ca(2+) signals that travel to astrocytic processes (;endfeet') encasing parenchymal arterioles within the brain. Astrocytic Ca(2+) signals cause the release of vasoactive substances to cause relaxation, and in some circumstances contraction, of the smooth muscle cells (SMCs) of parenchymal arterioles to modulate local cerebral blood flow. Activation of potassium channels in the SMCs has been proposed to mediate NVC. Here, the current state of knowledge of NVC and potassium channels in parenchymal arterioles is reviewed.

Figure 1

Pial arteries on the surface of the brain penetrate into the cortical parenchyma to give rise to parenchymal arterioles. Pial arteries are extrinsically innervated by sympathetic nerves (shown in white). As the arteriole penetrates into the brain parenchyma beyond the Virchow-Robin space, extrinsic innervation is lost and the arteriole becomes completely encased in astrocytic terminal processes called ‘endfeet’. Astrocytes integrate information from neurons and other cell types (ie, interneurons) and translate that information into dynamic astrocytic Ca²⁺ signals that propagate to the endfoot and regulate parenchymal arteriolar tone in order to regulate local cerebral blood flow according to the metabolic needs of the surrounding tissue.

Figure 2

Illustration depicting the involvement of parenchymal arteriolar smooth muscle cell (SMC) K⁺ channels in putative mechanisms of neurovascular coupling. Neuronal activity stimulates astrocytic metabotropic glutamate receptors (not shown) to produce a propagating rise in [Ca²⁺]_i that terminates in perivascular endfeet. Increased astrocytic endfoot [Ca²⁺] activates BK channels to release K⁺ into the perivascular cleft. Moderate elevations in [K⁺]_o in the perivascular cleft activate Kir channels in parenchymal arteriole SMCs, resulting in SMC membrane potential hyperpolarization, decreased Ca²⁺ entry through VDCCs, decreased [Ca²⁺]_i, and vasodilation. Increased astrocytic endfoot [Ca²⁺] also activates the Ca²⁺ sensitive enzyme cytosolic phoshpolipase A2 (PLA2). PLA2 hydrolyzes membrane phospholipids to release the fatty acid arachidonic acid (AA). AA is then metabolized by cyclooxygenase (COX) and prostaglandin synthases to yield PGE2, or is believed to diffuse to the parenchymal arteriole SMC, where it is metabolized by cytochrome P-450 enzymes to generate EETs and/or 20-HETE. The mechanism of action of PGE2 on parenchymal arteriole SMCs is unknown, but based on studies done in pial arteries, it might involve cAMP-dependent activation of SMC BK channels, and subsequent SMC hyperpolarization and vasodilation. EETs formed in arteriolar SMCs by the metabolism of astrocytederived AA are proposed to activate SMC BK channels to elicit membrane hyperpolarization and vasodilation. Conversely, 20-HETE is believed to inhibit parenchymal arteriolar SMC BK channels resulting in membrane depolarization, activation of VDCCs, elevation of [Ca²⁺]_i, and vasoconstriction.