Maxadilan, a PAC1 receptor agonist from sand flies

Abstract

In 1991, a potent 61 amino acid vasodilator peptide, named maxadilan, was isolated from the salivary glands of the sand fly. Subsequently, it was shown that this peptide specifically and potently activated the mammalian PAC1 receptor, one of the three receptors for PACAP. These studies and the link between maxadilan and leishmaniasis are discussed. Keywordsmaxadilan; PAC1; receptor; PACAP; leishmaniasis Identification of maxadilan and its mammalian receptor.Blood-feeding or hematophagous insects express vasoactive compounds in their salivary glands. These compounds serve to counteract the hemostatic processes of the host when the insect obtains a blood meal. The bite of the New World sand fly Lutzomyia longipalpis, a vector of the protozoan disease leishmaniasis, results in the rapid development of a small area of long-lasting redness or erythema at the site (Fig. 1). Erythema is typically associated with vasodilatation. Lerner et al. [4] isolated the vasoactive principle responsible for this effect. Reversed-phase HPLC was used to fractionate sand fly salivary gland extracts. The fractions were injected into the skin of rabbits and activity was determined by the presence or absence of erythema. The erythema-inducing fraction was shown to contain a vasodilatory peptide, named, because of its high potency, maxadilan.The sand fly gene encoding maxadilan was cloned and sequenced a year later [5]. Maxadilan is a vasodilator 500 times more potent than calcitonin gene-related peptide (CGRP) [4], the most potent peptide described at that time. Furthermore, the erythema induced by picogram quantities of maxadilan injected into human skin persists for approximately 48 hours. The vasodilatory properties of maxadilan were subsequently shown to be endothelium-independent and to be, at least in part, mediated by alterations in the levels of intracellular cAMP in smooth muscle cells. In addition to its action on cutaneous vessels, maxadilan also had vasodilatory activity on rabbit aorta and mesenteric artery [2].Maxadilan was demonstrated to bind to brain extracts from various species including human and mouse [9]. It also bound to neural crest-derived cell lines including the rat pheochromocytoma line PC12, and the human neuroblastoma line NBfl [10]. These results suggested that maxadilan could activate one of the receptors for vasoactive neuropeptides. The CGRP receptors were the initial candidates, because CGRP appeared to induce a similar clinical Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers

Differential Activation of Guinea Pig Intrinsic Cardiac Neurons by the PAC1 Agonists Maxadilan and Pituitary Adenylate Cyclase-Activating Polypeptide 27 (PACAP27)

“…Maxadilan is a unique natural peptide that is present in the salivary gland of the sand fly Lutzomyia longipalpis, and transfer of the peptide to humans during bloodfeeding causes a "persistent vasodilator" response of the skin (Moro and Lerner, 1997;Lerner et al, 2007). Although maxadilan has no sequence homology with PACAP, it binds selectively to (PACAP, n ϭ 10; maxadilan, n ϭ 9; and VIP, n ϭ 7).…”

“…In contrast, PACAP receptors (i.e., PAC1) have a very low affinity for VIP but exhibit a high affinity for PACAP27 and PACAP38. Structural analogs of VIP have been developed as selective agonists for VPAC1 and VPAC2 receptors, whereas the only selective PAC1 receptor agonist is a peptide named maxadilan, which was isolated from the sand fly and has no sequence homology with PACAP (Vaudry et al, 2000;Laburthe and Couvineau, 2002;Lerner et al, 2007).…”

Pituitary Adenylate Cyclase-Activating Polypeptide and Its Receptors: 20 Years after the Discovery

“…A natural 61-amino acid polypeptide called maxadilan has been isolated from the salivary gland of the bloodfeeding sand fly Lutzomia lingipalpis on the basis of its vasodilatory activity (Lerner et al, 1991) and has been characterized as a potent selective agonist of PAC1-R (Table 4) (Moro and Lerner, 1997;Lerner et al, 2007).…”

Migraine, Neurogenic Inflammation, Drug Development - Pharmacochemical Aspects

“…Maxadilan is a 61 amino acid protein, a potent vasodilator isolated from the saliva of sand flies [118]. The maxadilan binding site was found to be the PAC 1 receptor, making maxadilan a PACAP1-38 receptor agonist [119]. Deletion of amino-acids between position 24 and 42 generated M65, a potent and selective PAC 1 antagonist [120].…”