T-type Calcium Channels: Functional Regulation and Implication in Pain Signaling

Abstract

Abstract. Low-voltage-activated T-type Ca2+ channels (T-channels), especially Ca v 3.2 among the three isoforms (Ca v 3.1, Ca v 3.2, and Ca v 3.3), are now considered to play pivotal roles in processing of pain signals. Ca v 3.2 T-channels are functionally modulated by extracellular substances such as hydrogen sulfide and ascorbic acid, by intracellular signaling molecules including protein kinases, and by glycosylation. Ca v 3.2 T-channels are abundantly expressed in both peripheral and central endings of the primary afferent neurons, regulating neuronal excitability and release of excitatory neurotransmitters such as substance P and glutamate, respectively. Functional upregulation of Ca v 3.2 T-channels is involved in the pathophysiology of inflammatory, neuropathic, and visceral pain. Thus, Ca v 3.2 T-channels are considered to serve as novel targets for development of drugs for treatment of intractable pain resistant to currently available analgesics.

Hydrogen Sulfide and T-Type Ca²⁺ Channels in Pain Processing, Neuronal Differentiation and Neuroendocrine Secretion

“…It has been reported that CSE and CBS are upregulated in inflammatory conditions such as sepsis, pancreatitis and cystitis in rats or mice [25][26][27][28] . On the other hand, Ca v 3.2 targeted by H 2 S is upregulated de novo or functionally in the DRG and/or spinal cord in laboratory animals with surgically induced neuropathic pain [15,[29][30][31][32][33] . In mice or rats, intraplantar and intracolonic administration of NaHS, an H 2 S donor, evokes mechanical hyperalgesia/allodynia and visceral nociceptive behavior accompanied by re- 198 ferred hyperalgesia, respectively, which are blocked by Ttype Ca 2+ blockers or gene silencing of Ca v 3.2 [8,11,29,34,35] .…”

“…In the nociceptor neurons, H 2 S enhances the function of Ca v 3.2 T-type Ca 2+ channels [8][9][10][11][12] and TRPA1 channels [13,14] , leading to the neuronal excitation and then pain sensation or hyperalgesia/allodynia [3,7,15] . We have also shown that the acceleration of Ca v 3.2 channel activity by exogenous H 2 S causes neuritogenesis and neuronal differentiation in NG108-15 cells [9,10,16] , and that the endogenous H 2 S/ Ca v 3.2 pathway regulates secretory function in the neuroendocrine-like differentiated human prostate cancer LNCaP cells [17] .…”

Functional importance of T-type voltage-gated calcium channels in the cardiovascular and renal system: news from the world of knockout mice

“…In contrast to the expression data, a recent study found no T-type currents in either afferent or efferent arteriole rat myocytes (97), although high-voltage activated currents were observed in smooth muscle cells isolated from afferent arterioles. T-type currents were detected in the tail arteries in the same study (93). T-type currents have previously been measured in rat preglomerular vascular smooth muscle cells (29).…”

H2S and Pain: A Novel Aspect for Processing of Somatic, Visceral and Neuropathic Pain Signals

“…It is consistent with the evidence that H 2 S stimulates capsaicin-sensitive primary afferent nerve terminals, from which tachykinins are released to produce concentration-dependent contractile responses by activating NK 1 and NK 2 receptors in the rat urinary bladder (Patacchini et al 2004). Nonetheless, TRPV1 is not considered a direct target for H 2 S, and Ca v 3.2 T-type Ca 2+ channels and transient receptor potential ankyrin-1(TRPA1) rather appear responsible for excitation of sensory neurons (Miyamoto et al 2011;Andersson et al 2012;Pozsgai et al 2012;Sekiguchi and Kawabata 2013;Donatti et al 2014). Sensory plasticity in nociception, known as sensitization, is thought to contribute significantly to the production of persistent, often pathological pain.…”

“…Bourinet and his coworkers have demonstrated thermal and mechanical analgesia in rats with molecular knockdown of Ca v 3.2 T-channels in DRG neurons (Bourinet et al 2005). Ca v 3.2 T-channels are much more sensitive to inhibition by metals, such as zinc, copper, and nickel, than Ca v 3.1 or Ca v 3.3 (Todorovic and Jevtovic-Todorovic 2011;Sekiguchi and Kawabata 2013). It is now clear that a histidine residue at position 191 (His191) in the second extracellular loop of domain I of Ca v 3.2 is a critical determinant for the trace metal inhibition and is not conserved in Ca v 3.1 or Ca v 3.3 (Iftinca and Zamponi 2009).…”