CGRP, a Vasodilator Neuropeptide that Stimulates Neuromuscular Transmission and EC Coupling

Abstract

Calcitonin gene related peptide (CGRP) is a vasodilator; its plasma levels are altered in several human diseases, including migraine, hypertension and diabetes. CGRP is locally released by motor neurons, and is overexpressed in response to surgical or pharmacological blockage of neuromuscular transmission. Additionally to a brief discussion with regard to the clinical relevance of CGRP, this review focuses on the effects of CGRP on skeletal muscle excitation-contraction (EC) coupling, as well as the corresponding pathophysiological consequences. EC coupling involves activation of 2 different types of calcium channels: dihydropyridine receptors (DHPRs) located at the sarcolemma, and ryanodine receptors (RyR1s) located at the sarcoplasmic reticulum (SR). In response to electrical depolarization, DHPRs activate nearby and physically bound RyR1s, allowing Ca(2+) from the SR to move into the cytosol (termed voltage-gated Ca(2+) release, or VGCR). We recently found that CGRP stimulates VGCR by 350 % in as short as 1h. This effect, which lasts for at least 48 h, is due to activation of the CGRP receptor, and requires activation of the cAMP/PKA signaling pathway. CGRP also increases the amplitude of caffeine-induced Ca(2+) release (400 %); suggesting increased SR Ca(2+) content underlies stimulation of VGCR. Interestingly, in the long-term CGRP also increases the density of sarcolemmal DHPRs (up to 30%, within 24-48 h). We propose that these CGRP effects may contribute to prevent and/or restore symptoms in central core disease (CCD); a congenital myopathy that is linked to mutations in the gene encoding RyR1.

α−Calcitonin gene-related peptide inhibits autophagy and calpain systems and maintains the stability of neuromuscular junction in denervated muscles

“…In agreement with the notion that CGRP exerts its physiological actions mainly through cAMP/PKA/CREB signaling pathway [4], [17], [38], we found that CGRP in vitro increased the cAMP levels as well as the phosphorylation levels of several PKA substrates, including CREB in both normal and DEN rat muscles (Figure 1A–F). cAMP levels increased rapidly within 15 min of CGRP in both control and denervated muscles but remained high until 120 min only in denervated muscles (Figure 1A,B).…”

“…Previously, we demonstrated that CGRP exerted its inhibitory actions on FoxO activity through PKA and not AKT [38]. PKA is well known to be involved in the physiological effects of this peptide [3], [4], [17]. Because mTORC1 can be stimulated by both AKT and PKA [60], [61] and negatively controls autophagy [26], [55], we investigated whether mTORC1 might be involved in the suppressive effects of CGRP on autophagy and on NMJ maintenance.…”

“…CGRP is widely distributed in the central and peripheral nervous systems, including sensory and motor neurons [3]. Motor neurons release CGRP at the neuromuscular junction (NMJ) of skeletal muscle, where it binds to CGRP receptors to induce both short and long-term actions mainly through cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/cAMP response element binding protein (CREB) signaling pathway [3], [4], [5], [6].…”

Glucocorticoid-induced CREB activation and myostatin expression in C2C12 myotubes involves phosphodiesterase-3/4 signaling

“…Protein kinase A (PKA), a major effector of cAMP in skeletal muscle, has an important role in muscle metabolism, including the phosphorylation of CREB on Ser-133 [ 26 ]. An increase in intracellular cAMP leads to activation of PKA which, in turn, phosphorylates CREB and other proteins [ 27 ]. Cyclic nucleotide phosphodiesterases (PDEs) catalyze the hydrolysis of cAMP and, therefore, reduce PKA activity.…”

Drugs Against Calcitonin Gene-Related Peptide and its Receptor Used in the Treatment of Migraine: What are the New Progresses?

“…CGRP seems to significantly stimulate the calcium (Ca ++ ) channels at the sarcoplasmic reticulum leading to Ca ++ release into the cytosol of the skeletal muscle and also stimulate the Ca ++ channels at the sarcolemma to a lesser extent. 129 CGRP expression increases in injured motor neurons and is believed to activate neuroglial cells such as astrocytes and microglial cells in the CNS which is believed to be responsible for tissue remodeling and repair.…”