Kruse LS, Sandholdt NT, Gammeltoft S, Olesen J, Kruuse CPhosphodiesterase 3 and 5 and cyclic nucleotide-gated ion channel expression in rat trigeminovascular system. Neurosci Lett 404:202-207

Department of Neurology, Glostrup Hospital, Nordre Ringvej 57, Denmark.
Neuroscience Letters (Impact Factor: 2.03). 09/2006; 404(1-2):202-7. DOI: 10.1016/j.neulet.2006.05.045
Source: PubMed

ABSTRACT Activation of the trigeminovascular pain signalling system appears involved in migraine pathophysiology. However, the molecular mechanisms are only partially known. Stimulation of cAMP and cGMP production as well as inhibition of their breakdown induce migraine-like headache. Additionally, migraine may be associated with mutations in ion channels. The aim of the present study was to describe the expression of phosphodiesterase 3 (PDE3) and 5 (PDE5) and cyclic nucleotide-gated ion channels (CNG) in cerebral arteries, meninges, and the trigeminal ganglion. mRNA for PDE and CNG was determined in the rat middle cerebral artery, basilar artery, trigeminal ganglion, and dura mater using real-time PCR. PDE and CNG proteins were identified using Western blot. For comparison, rat aorta and mesenteric artery were analysed. PDE3A, PDE3B, and PDE5A mRNA were detected in all tissues examined except for PDE3A mRNA in dura mater and the trigeminal ganglion. PDE5A and PDE3A protein expression was present in both cerebral and peripheral arteries, whereas PDE3B protein was present only in the cerebral arteries. The CNGA4 and B1 subunit mRNAs were detected in cerebral arteries and CNGA2 also in the mesenteric artery. CNGA2 and A3 proteins were found in cerebral arteries and dura and CNGA1, CNGA2 and CNGA3 in the trigeminal ganglion. In conclusion, PDE3A, PDE3B, PDE5A, and five CNG subunits were expressed in several components of the trigeminovascular system of the rat. This suggests that modulation of cAMP and cGMP levels by PDE and activation of CNG may play a role in trigeminovascular pain signalling leading to migraine headache.

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    • "There are three functional subunits CNGA1-A3. All these three subunits were reported to be expressed both in vascular endothelial cells and vascular smooth muscle cells [8], [9], [24]–[26]. Previous study also suggested that CNGA1 expression in vascular smooth muscle is very low, because RT-PCR could detect CNGA1 in cultured vascular smooth muscle cells but Western blot and in situ hybridization failed to detect CNGA1 in vascular tissues [9], [24]. In the present study, we found the expression of CNGA2 and A3, but not A1, in the protein lysates from rat vascular smooth muscle cell layers. "
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    ABSTRACT: Thromboxane A(2) (TxA(2))-induced smooth muscle contraction has been implicated in cardiovascular, renal and respiratory diseases. This contraction can be partly attributed to TxA(2)-induced Ca(2+) influx, which resulted in vascular contraction via Ca(2+)-calmodulin-MLCK pathway. This study aims to identify the channels that mediate TxA(2)-induced Ca(2+) influx in vascular smooth muscle cells. Application of U-46619, a thromboxane A(2) mimic, resulted in a constriction in endothelium-denuded small mesenteric artery segments. The constriction relies on the presence of extracellular Ca(2+), because removal of extracellular Ca(2+) abolished the constriction. This constriction was partially inhibited by an L-type Ca(2+) channel inhibitor nifedipine (0.5-1 microM). The remaining component was inhibited by L-cis-diltiazem, a selective inhibitor for CNG channels, in a dose-dependent manner. Another CNG channel blocker LY83583 [6-(phenylamino)-5,8-quinolinedione] had similar effect. In the primary cultured smooth muscle cells derived from rat aorta, application of U46619 (100 nM) induced a rise in cytosolic Ca(2+) ([Ca(2+)](i)), which was inhibited by L-cis-diltiazem. Immunoblot experiments confirmed the presence of CNGA2 protein in vascular smooth muscle cells. These data suggest a functional role of CNG channels in U-46619-induced Ca(2+) influx and contraction of smooth muscle cells.
    PLoS ONE 06/2010; 5(6):e11098. DOI:10.1371/journal.pone.0011098 · 3.23 Impact Factor
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    ABSTRACT: Alzheimer’s Disease (AD) is a disease of synaptic dysfunction that ultimately proceeds to neuronal death. There is a wealth of evidence that indicates the final common mediator of this neurotoxic process is the formation and actions on synaptotoxic b-amyloid (Aβ). The premise in this review is that synaptic dysfunction may also be an initiating factor in for AD and promote synaptotoxic Aβ formation. This latter hypothesis is consistent with the fact that the most common risk factors for AD, apolipoprotein E (ApoE) allele status, age, education, and fitness, encompass suboptimal synaptic function. Thus, the synaptic dysfunction in AD may be both cause and effect, and remediating synaptic dysfunction in AD may have acute effects on the symptoms present at the initiation of therapy and also slow disease progression. The cyclic nucleotide (cAMP and cGMP) signaling systems are intimately involved in the regulation of synaptic homeostasis. The phosphodiesterases (PDEs) are a superfamily of enzymes that critically regulate spatial and temporal aspects of cyclic nucleotide signaling through metabolic inactivation of cAMP and cGMP. Thus, targeting the PDEs to promote improved synaptic function, or ‘synaptic resilience’, may be an effective and facile approach to new symptomatic and disease modifying therapies for AD. There continues to be a significant drug discovery effort aimed at discovering PDE inhibitors to treat a variety of neuropsychiatric disorders. Here we review the current status of those efforts as they relate to potential new therapies for AD. KeywordsAlzheimer’s disease-Phosphodiesterase-Cyclic nucleotide-Synaptic plasticity-PDE2A-PDE4-PDE5A-PDE7-PDE8B-PDE9A
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