title: Loss of inhibition by brain natriuretic peptide over P2X3 receptors contributes to enhanced spike firing of trigeminal ganglion neurons in a mouse model of familial hemiplegic migraine type-1.
abstract: Purinergic P2X3 receptors (P2X3Rs) play an important role in pain pathologies, including migraine. In trigeminal neurons, P2X3Rs are constitutively downregulated by endogenous brain natriuretic peptide (BNP). In a mouse knock-in (KI) model of familial hemiplegic migraine type-1 with upregulated calcium CaV2.1 channel function, trigeminal neurons exhibit hyperexcitability with gain-of-function of P2X3Rs and their deficient BNP-mediated inhibition. We studied whether the absent BNP-induced control over P2X3Rs activity in KI cultures may be functionally expressed in altered firing activity of KI trigeminal neurons. Patch-clamp experiments investigated the excitability of wild-type and KI trigeminal neurons induced by either current or agonists for P2X3Rs or transient receptor potential vanilloid-1 (TRPV1) receptors. Consistent with the constitutive inhibition of P2X3Rs by BNP, sustained pharmacological block of BNP receptors selectively enhanced P2X3R-mediated excitability of wild-type neurons without affecting firing evoked by the other protocols. This effect included increased number of action potentials, lower spike threshold and shift of the firing pattern distribution toward higher spiking activity. Thus, inactivation of BNP signaling transformed the wild-type excitability phenotype into the one typical for KI. BNP receptor block did not influence excitability of KI neurons in accordance with the lack of BNP-induced P2X3R modulation. Our study suggests that, in wild-type trigeminal neurons, negative control over P2X3Rs by the BNP pathway is translated into tonic suppression of P2X3Rs-mediated excitability. Lack of this inhibition in KI cultures results in a hyperexcitability phenotype and might contribute to facilitated trigeminal pain transduction relevant for migraine.
authors.affiliation: Neuroscience Department, International School for Advanced Studies (SISSA), Via Bonomea 265, 34136 Trieste, Italy. Electronic address: marchenkova.anna@sissa.it.
authors.forename: Anna
authors.initials: A
authors.lastname: Marchenkova
authors.affiliation: Department of Neurology, Leiden University Medical Centre, Leiden, Netherlands; Department of Human Genetics, University Medical Centre, Leiden, Netherlands. Electronic address: maagdenberg@lumc.nl.
authors.forename: Arn M J M
authors.initials: AM
authors.lastname: van den Maagdenberg
authors.affiliation: Neuroscience Department, International School for Advanced Studies (SISSA), Via Bonomea 265, 34136 Trieste, Italy. Electronic address: nistri@sissa.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Nistri
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D002478:Cells, Cultured; D002524:Cerebellar Ataxia / Q000378:metabolism*; D004195:Disease Models, Animal; D004558:Electric Stimulation; D008822:Mice, Transgenic; D008881:Migraine Disorders / Q000378:metabolism*; D020097:Natriuretic Peptide, Brain / Q000378:metabolism*; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010456:Peptides, Cyclic / Q000494:pharmacology; D017461:Receptors, Atrial Natriuretic Factor / Q000378:metabolism; D058477:Receptors, Purinergic P2X3 / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000819:agonists / Q000378:metabolism; D012668:Trigeminal Ganglion / Q000187:drug effects / Q000378:metabolism*
chemical_list: D018377:Neurotransmitter Agents; D010456:Peptides, Cyclic; D058477:Receptors, Purinergic P2X3; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D020097:Natriuretic Peptide, Brain; C068090:anantin; D000255:Adenosine Triphosphate; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A; C002630:alpha,beta-methyleneadenosine 5'-triphosphate; D002211:Capsaicin
keywords: TRPV1; nociception; purinergic receptor; sensory neurons; vanilloid receptor