Functional Interaction among KCa and TRP Channels for Cardiovascular Physiology: Modern Perspectives on Aging and Chronic Disease

Figures

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  Figure 1. Anatomy of endothelium-derived hyperpolarization and myoendothelial coupling. Endothelium: Physiological stimulation of endothelial Gq-protein-coupled receptors (GqPCRs; muscarinic (M3), purinergic (P2Y)) occurs through neurotransmitter secretion (parasympathetic nervous system (PSNS), acetylcholine (ACh); sympathetic nervous system (SNS), adenosine triphosphate (ATP)) or ATP release from red blood cells (RBCs) as primary examples. ACh and ATP are pharmacologically applied using bulk flow or focal delivery via pipettes (iontophoresis and pressure ejection). Following endothelial GqPCR activation, inositol 1,4,5-trisphosphate (IP3) is produced, which in turn activates IP3 receptors (IP3Rs) to release Ca2+ from the endoplasmic reticulum (ER) into the cytosol. ER Ca2+ release is observed as the initial “peak” response in ∆[Ca2+]i. The ER Ca2+ stores are filled or refilled through uptake of Ca2+ from the cytosol into the ER through smooth endoplasmic reticulum Ca2+ ATPase (SERCA) pumps to sustain repetitive physiological signaling. The influx of Ca2+ occurs through TRP channels (e.g., vanilloid class, TRPV4) to help refill ER Ca2+ stores while integral to the secondary “plateau”…

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  Figure 2. Functional contribution of major transient receptor potential (TRP) channel isoforms to activation of small- and intermediate-Ca2+-activated K+ (SKCa and IKCa) channels and endothelium-derived hyperpolarization. (A) Permeability of Ca2+ to Na+ ions (PCa/PNa) varies across the canonical (TRPC), vanilloid (TRPV), and ankyrin families of TRP channels. However, with the exception of TRPC1, endothelial TRP channels underlie significant influx of Ca2+ to activate SKCa and IKCa channels. As discussed in the text, note that these individual TRP isoforms can form tetrameric TRP channels via heteromeric combinations (e.g., TRPV4–TRPC1, TRPC3–TRPC4) in a physiological setting that may not be representative of determinations of homomeric channels expressed in heterologous culture systems. As it relates to the competition with Na+ influx, the “?” symbol indicates the unknown contribution of Ca2+ influx through TRPC1-containing channels for Vm depolarization vs. activation of SKCa and IKCa channels for Vm hyperpolarization as both are theoretically possible. Hyperpolarization via activation of SKCa/IKCa channels may stimulate Ca2+ influx through TRPV4-containing channels for further activation…

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  Figure 3. Working model for the upregulation of endothelium-derived hyperpolarization during aging and development of chronic pathology per enhanced oxidative signaling. Cardiovascular aging and the development of chronic disease is associated with a progressive increase in endothelial oxidative signaling. Mitochondrial respiration is a primary source of superoxide (O2•−) which inactivates NO to peroxynitrite (ONOO−) and, via superoxide dismutase, O2•− is rapidly converted to H2O2. H2O2/OH• activates SKCa and IKCa (primarily IKCa) channels directly and/or indirectly (Ca2+ influx through TRP channels). Thus, SKCa/IKCa channel function may “compensate” for decreased NO bioavailability to sustain local vasodilation. The (−) symbol indicates Vm hyperpolarization while the respective color of lines corresponds to O2•− (black), H2O2 (orange), or Ca2+ (red) signaling.