Calcitonin receptor‐like receptor (CLR), receptor activity‐modifying protein 1 (RAMP1), and calcitonin gene‐related peptide (CGRP) immunoreactivity in the rat trigeminovascular system: Differences between peripheral and central CGRP receptor distribution

Lennerz, Jochen K.; Rühle, Victor; Ceppa, Eugene P.; Neuhuber, Winfried; Bunnett, Nigel W.; Grady, Eileen F.; Meßlinger, Karl

doi:10.1002/cne.21653

Cited by 22 publications

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“…2010). The localization of CGRP receptors in the trigeminovascular system points to multiple possible mechanisms at both peripheral and central sites (Lennerz et al . 2008; Villalon & Olesen, 2009; Ho et al .…”

Section: Discussionmentioning

confidence: 99%

Trigeminal ganglion neuron subtype‐specific alterations of Ca_V2.1 calcium current and excitability in a Cacna1a mouse model of migraine

Fioretti

Catacuzzeno

Sforna

et al. 2011

The Journal of Physiology

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Non-technical summary Activation of trigeminal neurons innervating the meninges and release of proinflammatory peptides (in particular calcitonin gene-related peptide (CGRP)) from their terminals are believed to play a key role in generating migraine pain. A monogenic subtype of migraine (familial hemiplegic migraine type-1 (FHM1)) is caused by gain-of-function mutations in a neuronal voltage-gated calcium channel (Ca v 2.1) involved in controlling neurotransmitter release from many synaptic terminals including those of trigeminal neurons at the meninges. Using a FHM1 transgenic mouse model, we show that the migraine mutation produces gain-of-function (i.e. it increases calcium influx) in a subpopulation of trigeminal neurons that do not innervate the meninges. In contrast, the calcium channels of trigeminal neurons innervating the meninges and releasing CGRP are not affected by the mutation. Congruently, the migraine mutation does not alter CGRP release at the meninges. Our findings suggest that the facilitation of CGRP actions at the meninges does not contribute to the generation of headache in FHM1.Abstract Familial hemiplegic migraine type-1 (FHM1), a monogenic subtype of migraine with aura, is caused by gain-of-function mutations in Ca V 2.1 (P/Q-type) calcium channels. The consequences of FHM1 mutations on the trigeminovascular pathway that generates migraine headache remain largely unexplored. Here we studied the calcium currents and excitability properties of two subpopulations of small-diameter trigeminal ganglion (TG) neurons from adult wild-type (WT) and R192Q FHM1 knockin (KI) mice: capsaicin-sensitive neurons without T-type calcium currents (CS) and capsaicin-insensitive neurons characterized by the expression of T-type calcium currents (CI-T). Small TG neurons retrogradely labelled from the dura are mostly CS neurons, while CI-T neurons were not present in the labelled population. CS and CI-T neurons express Ca V 2.1 channels with different activation properties, and the Ca V 2.1 channels are differently affected by the FHM1 mutation in the two TG neuron subtypes. In CI-T neurons from FHM1 KI mice there was a larger P/Q-type current density following mild depolarizations, a larger action potential (AP)-evoked calcium current and a longer AP duration when compared to CI-T neurons from WT mice. In striking contrast, the P/Q-type current density, voltage dependence and kinetics were not altered by the FHM1 mutation in CS neurons. The excitability properties of mutant CS neurons were also unaltered. Congruently, the FHM1 mutation did not alter depolarization-evoked CGRP release from the dura mater, while CGRP release from the trigeminal ganglion was larger in KI compared to WT mice. Our findings suggest that the facilitation of peripheral mechanisms of CGRP action, such as dural vasodilatation and nociceptor sensitization at the meninges, does not contribute to the generation of headache in FHM1.

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Section: Discussionmentioning

confidence: 99%

Trigeminal ganglion neuron subtype‐specific alterations of Ca_V2.1 calcium current and excitability in a Cacna1a mouse model of migraine

Fioretti

Catacuzzeno

Sforna

et al. 2011

The Journal of Physiology

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“…The specificity of the commonly used anti-PGP9.5 and the antimast cell tryptase antibody has been shown in a variety of studies as summarized by Lennerz et al (2008). In particular, the anti-PGP9.5 antibody showed one band at 26–28 kDa on Western blot (Krimm et al, 2006).…”

Section: Methodsmentioning

confidence: 99%

Serotonin receptor diversity in the human colon: Expression of serotonin type 3 receptor subunits 5‐HT3C, 5‐HT3D, and 5‐HT3E

Kapeller

Möller

Lasitschka

et al. 2010

J of Comparative Neurology

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Since the first description of 5-HT 3 receptors more than 50 years ago, there has been speculation about the molecular basis of their receptor heterogeneity. We have cloned the genes encoding novel 5-HT3 subunits 5-HT3C, 5-HT3D, and 5-HT3E and have shown that these subunits are able to form functional heteromeric receptors when coexpressed with the 5-HT3A subunit. However, whether these subunits are actually expressed in human tissue remained to be confirmed. In the current study, we performed immunocytochemistry to locate the 5-HT3A as well as the 5-HT3C, 5-HT3D, and 5-HT3E subunits within the human colon. Western blot analysis was used to confirm subunit expression, and RT-PCR was employed to detect transcripts encoding 5-HT 3 receptor subunits in microdissected tissue samples. This investigation revealed, for the first time, that 5-HT3C, 5-HT3D, and 5-HT3E subunits are coexpressed with 5-HT3A in cell bodies of myenteric neurons. Furthermore, 5-HT3A and 5-HT3D were found to be expressed in submucosal plexus of the human large intestine. These data provide a strong basis for future studies of the roles that specific 5-HT 3 receptor subtypes play in the function of the enteric and central nervous systems and the contribution that specific 5-HT 3 receptors make to the pathophysiology of gastrointestinal disorders such as irritable bowel syndrome and dyspepsia.Keywords 5-HT receptor; 5-HT 3 ; ligand-gated ion channel; antibody; gastrointestinal tract Serotonin (5-hydroxytryptamine; 5-HT)-mediated signaling is important in bidirectional brain-gut interactions involved in cognition, emotions, and digestive function (Gershon and Tack, 2007). Most of the body's 5-HT (~95%) is produced and stored in enterochromaffin cells (EC) in the enteric mucosal epithelium; however, smaller stores of 5-HT are also present in the bowel in serotonergic neurons of the enteric nervous system (ENS), where 5-HT participates in both slow and fast neurotransmission (Gershon, 2004(Gershon, , 2005Gershon and Tack, 2007). After its release from EC cells or neurons, 5-HT stimulates the 5-HT 1 , 1 5-HT 2 , 5-HT 3 , 5-HT 4 , and 5-HT 7 subtypes of receptor, all of which are expressed in the gut. Animal studies have indicated that 5-HT activates submucosal intrinsic primary afferent neurons (IPANs) through 5-HT 1P receptors to initiate peristaltic reflexes (Pan and Gershon, 2000;Wade et al., 1994) and myenteric IPANs through 5-HT 3 receptors (Bertrand et al., 1997) to initiate giant migrating contractions (Karaus and Sarna, 1987;Nagakura et al., 2002;Sarna, 2007). 5-HT also stimulates 5-HT 4 receptors to increase secretion of acetylcholine and calcitonin gene-related peptide (CGRP;Grider, 2003). This 5-HT 4Copyright © 2010 Wiley-Liss, Inc.Correspondence to: Beate Niesler. 1 5-HT3 subunits and 5-HT 3 receptors are termed according to the Nomenclature Committee of the International Union of Pharmacology (NC-IUPHAR;Peters et al., 2010 (Liu et al., 2005;Pan and Galligan, 1994;Ren et al., 2008) and probably underlies the successful use of 5-HT...

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“…As mentioned, CGRP is widely expressed in the central and peripheral nervous systems where it appears to modulate the function of other neurotransmitters . In the trigeminal ganglion, it is often coexpressed with substance P and 5‐HT 1B/D receptors 51‐53. The satellite glial cells of the trigeminal ganglion also express CGRP receptors .…”

Section: Role Of Cgrp In Nociception and Neuronal Plasticitymentioning

confidence: 98%

Calcitonin Gene‐Related Peptide (CGRP) and Migraine Current Understanding and State of Development

2013

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Calcitonin gene-related peptide (CGRP) is a ubiquitous neuropeptide found at the very centers of the migraine process, both centrally and peripherally. It has been under careful study for approximately 25 years. Several CGRP-receptor antagonists are being evaluated for acute treatment of episodic migraine. Three monoclonal antibodies are being studied for prevention of episodic migraine, and 1 monoclonal antibody is being studied for prevention of chronic migraine. In this review, we discuss the role of CGRP in normal physiology and the consequences of CGRP inhibition for human homeostasis. We then review the current state of development for CGRP-receptor antagonists and CGRP monoclonal antibodies. We close by speculating on the potential clinical role of CGRP antagonism in the acute and preventive treatment of episodic and chronic migraine.Key words: calcitonin gene-related peptide, antibodies, migraine, chronic migraine (Headache 2013;53:1230-1244 Calcitonin gene-related peptide (CGRP) is a 37-amino-acid neuropeptide that is derived from the gene encoding calcitonin by alternative splicing of mRNA and proteolytic processing of its precursor. 1,2Despite their common origin, calcitonin and CGRP are involved in totally different physiological processes in humans. While calcitonin is mainly related to calcium homeostasis and bone remodeling, CGRP is involved in vasodilation and sensory transmission.CGRP is found in literally every organ system in the body, 3 occurring in 2 isoforms, a-and b-CGRP. 4,5a-CGRP is the predominant form in the peripheral nervous system, while the b-isoform is mainly present in the enteric nervous system. 6 CGRP is highly conserved across species, 7 suggesting that the neuropeptide is of importance in functions that were established relatively early in mammalian evolution.Immunohistochemistry demonstrated that CGRP is mainly produced in the cell bodies of both ventral and dorsal root neurons.8 Radioimmunology further demonstrated that this molecule is especially common in the trigeminal system, where up to 50% of the neurons produce it.9 Indeed, the potential role of CGRP in migraine pathophysiology was suggested more than 20 years ago, 10,11 and since then, our knowledge of the peptide and its role in the pathophysiology of migraine has increased substantially and has

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Calcitonin receptor‐like receptor (CLR), receptor activity‐modifying protein 1 (RAMP1), and calcitonin gene‐related peptide (CGRP) immunoreactivity in the rat trigeminovascular system: Differences between peripheral and central CGRP receptor distribution

Cited by 22 publications

References 0 publications

Trigeminal ganglion neuron subtype‐specific alterations of Ca_V2.1 calcium current and excitability in a Cacna1a mouse model of migraine

Trigeminal ganglion neuron subtype‐specific alterations of Ca_V2.1 calcium current and excitability in a Cacna1a mouse model of migraine

Serotonin receptor diversity in the human colon: Expression of serotonin type 3 receptor subunits 5‐HT3C, 5‐HT3D, and 5‐HT3E

Calcitonin Gene‐Related Peptide (CGRP) and Migraine Current Understanding and State of Development

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Calcitonin receptor‐like receptor (CLR), receptor activity‐modifying protein 1 (RAMP1), and calcitonin gene‐related peptide (CGRP) immunoreactivity in the rat trigeminovascular system: Differences between peripheral and central CGRP receptor distribution

Cited by 22 publications

References 0 publications

Trigeminal ganglion neuron subtype‐specific alterations of CaV2.1 calcium current and excitability in a Cacna1a mouse model of migraine

Trigeminal ganglion neuron subtype‐specific alterations of CaV2.1 calcium current and excitability in a Cacna1a mouse model of migraine

Serotonin receptor diversity in the human colon: Expression of serotonin type 3 receptor subunits 5‐HT3C, 5‐HT3D, and 5‐HT3E

Calcitonin Gene‐Related Peptide (CGRP) and Migraine Current Understanding and State of Development

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Trigeminal ganglion neuron subtype‐specific alterations of Ca_V2.1 calcium current and excitability in a Cacna1a mouse model of migraine

Trigeminal ganglion neuron subtype‐specific alterations of Ca_V2.1 calcium current and excitability in a Cacna1a mouse model of migraine