Lee RH, Liu YQ, Chen PY, Liu CH, Chen MF, Lin HW, Kuo JS, Premkumar LS, Lee TJ. Sympathetic ␣3␤2-nAChRs mediate cerebral neurogenic nitrergic vasodilation in the swine. Am J Physiol Heart Circ Physiol 301: H344 -H354, 2011. First published May 2, 2011; doi:10.1152/ajpheart.00172.2011.-The ␣7-nicotinic ACh receptor (␣7-nAChR) on sympathetic neurons innervating basilar arteries of pigs crossed bred between Landrace and Yorkshire (LY) is known to mediate nicotine-induced, ␤-amyloid (A␤)-sensitive nitrergic neurogenic vasodilation. Preliminary studies, however, demonstrated that nicotine-induced cerebral vasodilation in pigs crossbred among Landrace, Yorkshire, and Duroc (LYD) was insensitive to A␤ and ␣-bungarotoxin (␣-BGTX). We investigated nAChR subtype on sympathetic neurons innervating LYD basilar arteries. Nicotine-induced relaxation of porcine isolated basilar arteries was examined by tissue bath myography, inward currents on nAChR-expressing oocytes by two-electrode voltage recording, and mRNA and protein expression in the superior cervical ganglion (SCG) and middle cervical ganglion (MCG) by reverse transcription PCR and Western blotting. Nicotine-induced basilar arterial relaxation was not affected by A␤, ␣-BGTX, and ␣-conotoxin IMI (␣7-nAChR antagonists), or ␣-conotoxin AuIB (␣3␤4-nAChR antagonist) but was inhibited by tropinone and tropane (␣3-containing nAChR antagonists) and ␣-conotoxin MII (selective ␣ 3␤2-nAChR antagonist). Nicotine-induced inward currents in ␣ 3␤2-nAChR-expressing oocytes were inhibited by ␣-conotoxin MII but not by ␣-BGTX, A␤, or ␣-conotoxin AuIB. mRNAs of ␣ 3-, ␣7-, ␤2-, and ␤4-subunits were expressed in both SCGs and MCGs with significantly higher mRNAs of ␣ 3-, ␤2-, and ␤ 4-subunits than that of ␣7-subunit. The A␤-insensitive sympathetic ␣ 3␤2-nAChR mediates nicotine-induced cerebral nitrergic neurogenic vasodilation in LYD pigs. The different finding from A␤-sensitive ␣ 7-nAChR in basilar arteries of LY pigs may offer a partial explanation for different sensitivities of individuals to A␤ in causing diminished cerebral nitrergic vasodilation in diseases involving A␤.␣ 3␤2-nicotinic ACh receptor; axo-axonal interaction; ␤-amyloid; cerebral perivascular sympathetic nerves; superior cervical ganglion IT IS WELL ESTABLISHED THAT cerebral arteries receive dense sympathetic innervation originating in the superior cervical ganglion (SCG) (24, 50) and that nicotinic ACh receptors (nAChRs) on the nerve terminals regulate norepinephrine (NE) release (50). In the pigs crossbred between Landrace and Yorkshire in the United States, activation by nicotinic agonists of the nAChRs on perivascular sympathetic nerves innervating cerebral arteries results in release of NE, which then causes release of nitric oxide (NO) from the nearby parasympathetic nitrergic nerves and dilation of the arteries (22, 39). This nicotinic agonist-induced axo-axonal interaction leading to nitrergic vasodilation is mediated by the ␣ 7 -nAChR subtype (39). The vasodilation is blocked by ␤-amyloid peptide (A␤) via inhib...

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Memantine, an NMDA receptor antagonist used for treatment of Alzheimer’s disease (AD), is known to block the nicotinic acetylcholine receptors (nAChRs) in the central nervous system (CNS). In the present study, we examined by wire myography if memantine inhibited α3β2-nAChRs located on cerebral perivascular sympathetic nerve terminals originating in the superior cervical ganglion (SCG), thus, leading to inhibition of nicotine-induced nitrergic neurogenic dilation of isolated porcine basilar arteries. Memantine concentration-dependently blocked nicotine-induced neurogenic dilation of endothelium-denuded basilar arteries without affecting that induced by transmural nerve stimulation, sodium nitroprusside, or isoproterenol. Furthermore, memantine significantly inhibited nicotine-elicited inward currents in Xenopous oocytes expressing α3β2-, α7- or α4β2-nAChR, and nicotine-induced calcium influx in cultured rat SCG neurons. These results suggest that memantine is a non-specific antagonist for nAChR. By directly inhibiting α3β2-nAChRs located on the sympathetic nerve terminals, memantine blocks nicotine-induced neurogenic vasodilation of the porcine basilar arteries. This effect of memantine is expected to reduce the blood supply to the brain stem and possibly other brain regions, thus, decreasing its clinical efficacy in the treatment of Alzheimer’s disease.

Interruption of the perivascular sympathetic nerves can alleviate CA-induced hypoperfusion and neuronal cell death in the CA1 region of the hippocampus to enhance functional learning and memory.

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Arginine methylation is a post-translational process that is involved in epigenetic regulation, mRNA splicing, cell signaling, protein ubiquitination, phosphorylation, and acetylation (Kandel, 2001).The protein arginine methyltransferase (PRMT) family of enzymes are responsible for the transfer of methyl groups onto target arginine residues (e.g., RGG/RG motifs) on proteins, to result in a variety of cellular and protein signaling responses (Blanc & Richard, 2017). Recent studies have been focused on understanding PRMT function in various pathologies; however, the exact role of PRMTs has not been well elucidated in neurological function