Synaptobrevin I mediates exocytosis of CGRP from sensory neurons and inhibition by botulinum toxins reflects their anti-nociceptive potential
ABSTRACT Calcitonin-gene-related peptide (CGRP), a potent vasodilator that mediates inflammatory pain, is elevated in migraine; nevertheless, little is known about its release from sensory neurons. In this study, CGRP was found to occur in the majority of neurons from rat trigeminal ganglia, together with the three exocytotic SNAREs [SNAP25, syntaxin 1 and the synaptobrevin (Sbr, also known as VAMP) isoforms] and synaptotagmin. Ca(2+)-dependent CGRP release was evoked with K(+)-depolarisation and, to lower levels, by capsaicin or bradykinin from neurons that contain the vanilloid receptor 1 and/or bradykinin receptor 2. Botulinum neurotoxin (BoNT) type A cleaved SNAP25 and inhibited release triggered by K(+) > bradykinin > capsaicin. Unlike BoNT type D, BoNT type B did not affect exocytosis, even though the neurons possess its receptor and Sbr II and Sbr III got proteolysed (I is resistant in rat) but, in mouse neurons, it additionally cleaved Sbr I and blocked transmitter release. Sbr I and II were found in CGRP-containing vesicles, and each was shown to separately form a SNARE complex. These new findings, together with punctate staining of Sbr I and CGRP in neurites, implicate isoform Sbr I in exocytosis from large dense-core vesicles together with SNAP25 (also, probably, syntaxin 1 because BoNT type C1 caused partial cleavage and inhibition); this differs from Sbr-II-dependent release of transmitters from small synaptic vesicles. Such use of particular Sbr isoform(s) by different neurons raises the functional implications for other cells previously unrecognised.
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ABSTRACT: Calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide. Discovered 30 years ago, it is produced as a consequence of alternative RNA processing of the calcitonin gene. CGRP has two major forms (α and β). It belongs to a group of peptides that all act on an unusual receptor family. These receptors consist of calcitonin receptor-like receptor (CLR) linked to an essential receptor activity modifying protein (RAMP) that is necessary for full functionality. CGRP is a highly potent vasodilator and, partly as a consequence, possesses protective mechanisms that are important for physiological and pathological conditions involving the cardiovascular system and wound healing. CGRP is primarily released from sensory nerves and thus is implicated in pain pathways. The proven ability of CGRP antagonists to alleviate migraine has been of most interest in terms of drug development, and knowledge to date concerning this potential therapeutic area is discussed. Other areas covered, where there is less information known on CGRP, include arthritis, skin conditions, diabetes, and obesity. It is concluded that CGRP is an important peptide in mammalian biology, but it is too early at present to know if new medicines for disease treatment will emerge from our knowledge concerning this molecule.Physiological Reviews 10/2014; 94(4):1099-1142. DOI:10.1152/physrev.00034.2013 · 29.04 Impact Factor
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ABSTRACT: It is now clearly recognized that the function of the lower urinary tract represents a complex interaction between the bladder and its outlet, acting under the control of the central nervous system. While in the past attention has principally focused on the motor (efferent) control of the bladder, sensory (afferent) innervation is now known to be an important therapeutic target. This change in emphasis is strongly supported by both basic science and clinical evidence demonstrating the efficacy of therapy directed at the afferent system. This chapter summarizes the neurophysiological control mechanism that underpins normal lower urinary tract function, emphasizing the importance of the afferent system as a potential therapeutic target. Neurourol. Urodynam. 33:S6-S13, 2014. © 2014 Wiley Periodicals, Inc.Neurourology and Urodynamics 07/2014; 33 Suppl 3(S3):S6-S13. DOI:10.1002/nau.22635 · 2.67 Impact Factor
Article: Migren Tedavisinde Botulinum ToksiniNoropsikiyatri Arsivi 08/2013; 50(1):36-40. DOI:10.4274/npa.y7198 · 0.13 Impact Factor