Specific functioning of Cav3.2 T-type calcium and TRPV1 channels under different types of STZ-diabetic neuropathy

Abstract

Streptozotocin (STZ)-induced type 1 diabetes in rats leads to the development of peripheral diabetic neuropathy (PDN) manifested as thermal hyperalgesia at early stages (4th week) followed by hypoalgesia after 8weeks of diabetes development. Here we found that 6-7 week STZ-diabetic rats developed either thermal hyper- (18%), hypo- (25%) or normalgesic (57%) types of PDN. These developmentally similar diabetic rats were studied in order to analyze mechanisms potentially underlying different thermal nociception. The proportion of IB4-positive capsaicin-sensitive small DRG neurons, strongly involved in thermal nociception, was not altered under different types of PDN implying differential changes at cellular and molecular level. We further focused on properties of T-type calcium and TRPV1 channels, which are known to be involved in Ca(2+) signaling and pathological nociception. Indeed, TRPV1-mediated signaling in these neurons was downregulated under hypo- and normalgesia and upregulated under hyperalgesia. A complex interplay between diabetes-induced changes in functional expression of Cav3.2 T-type calcium channels and depolarizing shift of their steady-state inactivation resulted in upregulation of these channels under hyper- and normalgesia and their downregulation under hypoalgesia. As a result, T-type window current was increased by several times under hyperalgesia partially underlying the increased resting [Ca(2+)]i observed in the hyperalgesic rats. At the same time Cav3.2-dependent Ca(2+) signaling was upregulated in all types of PDN. These findings indicate that alterations in functioning of Cav3.2 T-type and TRPV1 channels, specific for each type of PDN, may underlie the variety of pain syndromes induced by type 1 diabetes.

Painful Diabetic Neuropathy

“…In contrast, a study by Pabbidi and colleagues demonstrated increased expression of TRPV1 protein and greater whole-cell current in small DRG cells in both STZ-induced and transgene-mediated type 1 painful PDN in mice (Pabbidi et al, 2008). Consistent with increased function of TRPV1 in DRG cells expressing T-currents, capsaicin-gated currents were increased in medium-size (Jagodic et al, 2007) and small DRG cells (Khomula et al, 2013; Shankarappa et al, 2011) from STZ-induced diabetic rats with painful PDN. This observation underscores the importance of possible cross-talk between nociceptive ligand and voltage-gated ion channels that control calcium signaling in DRG cells.…”

“…The current-voltage relationship in these cells was not different between control, healthy rats and experimental diabetic rats. Similarly, studies with streptozotocin (STZ)-induced diabetic neuropathy, which used electrophysiological recordings from acutely isolated IB 4 -positive medium and small size DRG cells, found that T-current amplitude was up-regulated about two-fold (Cao et al, 2011; Jagodic et al, 2007; Khomula et al, 2013). In addition, these three studies have shown that biophysical properties of T-channels were altered in DRG cells from diabetic animals, with a significant depolarizing shift in steady-state inactivation curves.…”

“…In addition, these three studies have shown that biophysical properties of T-channels were altered in DRG cells from diabetic animals, with a significant depolarizing shift in steady-state inactivation curves. As a result of this shift, more T-channels were available at physiological membrane potentials, and this increased propensity for burst firing in DRG cells from diabetic rats as compared with healthy ones (Jagodic et al, 2007; Khomula et al, 2013). …”

Diabetic neuropathies

“…The transient receptor potential ankyrin 1 (TRPA1) ion channel on primary afferent nerve fibers also appears involved in painful diabetic neuropathy, due to sustained activation by reactive compounds generated in diabetes [19]. Alterations in DRG Ca(v)3.2 T-type and TRPV1 channel function may also contribute to the variety of pain syndromes induced by type 1 diabetes [20]. In diabetes, up-regulation of cutaneous NGF may overstimulate surviving axons, which may participate in the genesis of painful diabetic neuropathy.…”

Qiliqiangxin Rescues Mouse Cardiac Function by Regulating AGTR1/TRPV1-Mediated Autophagy in STZ-Induced Diabetes Mellitus

“…Indeed, defects of TRPV1 have been associated with the occurrence of heart failure in type 1 and 2 diabetes mellitus due to their effects on ROS production, Ca 2+ transients, eNOS activity, adiponectin and leptin signaling control, the modulation of neuronal activity, microcirculatory vasodilation, and the regulation of myocardial blood flow [12,[29][30][31][32]. Direct induction of neurotransmitters downstream of TRPV1, such as CGRP and SP, leads to lowered LVEDP and increased LVSP, ± dP/dt, and coronary flow in diabetic mice [33].…”