TLQP-21, A VGF-Derived Peptide Endowed of Endocrine and Extraendocrine Properties: Focus on In Vitro Calcium Signaling

Abstract

VGF gene encodes for a neuropeptide precursor of 68 kDa composed by 615 (human) and 617 (rat, mice) residues, expressed prevalently in the central nervous system (CNS), but also in the peripheral nervous system (PNS) and in various endocrine cells. This precursor undergoes proteolytic cleavage, generating a family of peptides different in length and biological activity. Among them, TLQP-21, a peptide of 21 amino acids, has been widely investigated for its relevant endocrine and extraendocrine activities. The complement complement C3a receptor-1 (C3aR1) has been suggested as the TLQP-21 receptor and, in different cell lines, its activation by TLQP-21 induces an increase of intracellular Ca²⁺. This effect relies both on Ca²⁺ release from the endoplasmic reticulum (ER) and extracellular Ca²⁺ entry. The latter depends on stromal interaction molecules (STIM)-Orai1 interaction or transient receptor potential channel (TRPC) involvement. After Ca²⁺ entry, the activation of outward K⁺-Ca²⁺-dependent currents, mainly the K_Ca3.1 currents, provides a membrane polarizing influence which offset the depolarizing action of Ca²⁺ elevation and indirectly maintains the driving force for optimal Ca²⁺ increase in the cytosol. In this review, we address the main endocrine and extraendocrine actions displayed by TLQP-21, highlighting recent findings on its mechanism of action and its potential in different pathological conditions.

Keywords: KCa3.1 current; TLQP-21; VGF; calcium (Ca2+); calcium release-activated calcium channel (CRAC)-Orai1; complement C3a receptor-1 (C3aR1); endocrine; extraendocrine; stromal interaction molecules (STIM); transient receptor potential channel (TRPC).

Figure 1

Schematic representation of VGF and of VGF-derived peptides.

Figure 2

Schematic representation of TLQP-21 intracellular transduction mechanism in Chinese Hamster Ovary (CHO-K1) cells. TLQP-21, by binding a G protein coupled receptor (GPCR), activates Phospholipase C (PLC)-β that in turn produces Diacylglycerol (DAG) and Inositol Trisphosphate (IP3) as second messengers. These molecules activate Protein kinase C (PKC), stimulate extracellular signal-regulated kinase (ERK)1/2 phosphorylation and induce intracellular Ca²⁺ release from the endoplasmic reticulum (ER) with the subsequent Ca²⁺ entry from outside the cell, mediated by the stromal interaction molecules (STIM) and calcium release-activated calcium channel (CRAC)-Orai1 interaction. Phosphorylation of AKT is probably a result of the increase in cellular Ca²⁺ concentrations.