Central and peripheral contributions of T-type calcium channels in pain

Abstract

Chronic pain is a severely debilitating condition that reflects a long-term sensitization of signal transduction in the afferent pain pathway. Among the key players in this pathway are T-type calcium channels, in particular the Ca_v3.2 isoform. Because of their biophysical characteristics, these channels are ideally suited towards regulating neuronal excitability. Recent evidence suggests that T-type channels contribute to excitability of neurons all along the ascending and descending pain pathways, within primary afferent neurons, spinal dorsal horn neurons, and within pain-processing neurons in the midbrain and cortex. Here we review the contribution of T-type channels to neuronal excitability and function in each of these neuronal populations and how they are dysregulated in chronic pain conditions. Finally, we discuss their molecular pharmacology and the potential role of these channels as therapeutic targets for chronic pain.

Keywords: Analgesia; CACNA1H; Cav3.2; Glycosylation; Pain; T-type; Ubiquitination.

Fig. 1

Electrophysiological properties of T-type channels. a Typical inward current recorded from T-type channels during an IV-curve. Note that inward current in response to depolarization is rapidly activating and rapidly inactivating. b Typical steady state activation and inactivation curves for T-type channels. Current activation occurs near − 60 mV and reaches peak around − 20 mV. Overlap of activation and inactivation curves reveals a significant window current between -60 and -40 mV. c Adapted with permission from Joksimovic et al. [33]. Perfusion of 10 µM TTA-P2 significantly reduces burst firing in response to current injection (top) and rebound bursting (bottom) in subicular neurons, revealing the contribution of T-type channels to activity in these neurons

Fig. 2

Locations of T-type channels in the ascending afferent pain pathway. In rodents, T-type channels (green) are present surrounding D-hair mechanoreceptors, on both C and Aδ afferent fibers, on C and Aδ DRG somata, on C fiber presynaptic terminals, and on both lamina I and II neurons within the superficial dorsal horn. Insets indicate key experiments defining the presence of T-type channels in different compartments. a Expression of Cav3.2 fused to GFP in C and Aδ mouse sciatic nerve fibers. Adapted with permission from Francois et al. [67]. b Presence of low voltage-activated current in small diameter rat DRG neurons. Adapted with permission from Scroggs and Fox [59]. c T-type calcium channels contribute to action potential-induced calcium current in the soma and dendrites of rat lamina I neurons. Adapted with permission from Harding et al. [27]

Fig. 3

Known inhibitors of T-type channels with analgesic properties. a Left: structure of the high affinity and selectivity T-type channel inhibitor Z944. Right: Z944 shown within the binding pocket of Ca_v3.1. Adapted with permission from Zhao et al. [16]. b Structures of commonly utilized T-type channel inhibitors, with varying degrees of affinity and selectivity. Many of these compounds mediate analgesia in preclinical pain models