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 KCa3.1 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.
Highlights
Calcium (Ca2+) is a universal signaling molecule impacting nearly every aspect of cellular life by regulating a variety of cellular processes such as fertilization, gene transcription, cell proliferation, programmed cell death, neurotransmission, muscle contraction, and cell signaling [1]
The increase of the intracellular Ca2+ concentration can result from the activation of cation channels at the PM, like: (i) Transient receptor potential channels (TRPC), a large group of non-selective cation channels activated by a several stimuli and mostly permeable to Ca2+; (ii) Voltage-gated ion channels (VGCs), activated by changes in the electrical PM potential near the channel proteins or mechanosensitive channels; (iii) endoplasmic reticulum (ER)/SR-associated inositol-3-phosphate receptor (IP3R) and ryanodine-receptor (RyR) channels; and iv) Ca2+ release activated Ca2+ (CRAC) channels composed of two cellular proteins, Ca2+-sensing stromal interaction molecule 1 (STIM1) and pore-forming, Orai1
The depletion of intracellular Ca2+ stores is sensed by stromal interaction molecules (STIM) which interact with CRAC-Orai1, triggering store-operated Ca2+ entry (SOCE) currents, exploited to regulate basal Ca2+, to refill intracellular Ca2+ stores, and to execute a wide range of specialized activities
Summary
Calcium (Ca2+) is a universal signaling molecule impacting nearly every aspect of cellular life by regulating a variety of cellular processes such as fertilization, gene transcription, cell proliferation, programmed cell death, neurotransmission, muscle contraction, and cell signaling [1]. The Ca2+ ion could act as second messenger released inside the cells following the interaction of different endogenous molecules with their plasma membrane (PM) receptors. It can enter directly into the cells from the extracellular space to deliver information, without the intermediation of other first or second messengers. The increase of the intracellular Ca2+ concentration can result from the activation of cation channels at the PM, like: (i) Transient receptor potential channels (TRPC), a large group of non-selective cation channels activated by a several stimuli and mostly permeable to Ca2+; (ii) Voltage-gated ion channels (VGCs), activated by changes in the electrical PM potential near the channel proteins or mechanosensitive channels; (iii) ER/SR-associated inositol-3-phosphate receptor (IP3R) and ryanodine-receptor (RyR) channels; and iv) Ca2+ release activated Ca2+ (CRAC) channels composed of two cellular proteins, Ca2+-sensing stromal interaction molecule 1 (STIM1) and pore-forming, Orai. We provide an integrated view on the recent reports supporting the role of Ca2+ in mediating TLQP-21 mechanism of action
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