Calcium channel functions in pain processing

Park, John F.; Luo, Z. David

doi:10.4161/chan.4.6.12869

Cited by 122 publications

(113 citation statements)

References 138 publications

(167 reference statements)

Supporting

Mentioning

111

Contrasting

Order By: Relevance

“…Mutations in Ca v 3.2 T-type channels have been linked to absence seizures (Khosravani and Zamponi, 2006;Heron et al, 2007). Moreover, up-regulation of Ca v 3.2 T-type channel activity in primary afferent fibers has been linked to the development of chronic pain (for reviews, see Altier and Zamponi, 2004;Park and Luo, 2010), and T-type channel dysfunction contributes to cardiac hypertrophy (Cribbs, 2010;David et al, 2010). Both Na v channels and T-type channels contribute to neuronal excitability and to similar disorders such as epilepsy and pain.…”

Section: Introductionmentioning

confidence: 99%

Common Mechanisms of Drug Interactions with Sodium and T-Type Calcium Channels

Bladen¹,

Zamponi²

2012

Mol Pharmacol

View full text Add to dashboard Cite

Voltage-gated sodium (Na v ) and calcium (Ca v ) channels play important roles in physiological processes, including neuronal and cardiac pacemaker activity, vascular smooth muscle contraction, and nociception. They are thought to share a common ancestry, and, in particular, T-type calcium (T-type) channels share structural similarities with Na v channels, both with regard to membrane topology and with regard to gating kinetics, including rapid inactivation. We thus reasoned that certain drugs acting on Na v channels may also modulate the activities of T-type channels. Here we show that the specific Na v 1.8 blocker 5-(4-chlorophenyl-N-(3,5-dimethoxyphenyl)furan-2-carboxamide (A803467) tonically blocks T-type channels in the low micromolar range. Similarly to Na v 1.8, this compound causes a significant hyperpolarizing shift in the voltage dependence of inactivation and seems to promote a slow inactivation-like phenotype. We further hypothesized that the structural similarity between T-type and Na v channels may extend to structurally similar drug-binding sites. Sequence alignment revealed several highly conserved regions between T-type and Na v channels that corresponded to drug-binding sites known to alter voltage-dependent gating kinetics. Mutation of amino acid residues in this regions within human Ca v 3.2 T-type channels altered A803467 blocking affinity severalfold, suggesting that these sites may be exploited for the design of mixed T-type and Na v channel blockers that could potentially act synergistically to normalize aberrant neuronal activity.

show abstract

Section: Introductionmentioning

confidence: 99%

Common Mechanisms of Drug Interactions with Sodium and T-Type Calcium Channels

Bladen¹,

Zamponi²

2012

Mol Pharmacol

View full text Add to dashboard Cite

show abstract

“…[17][18][19][20][21] Along these lines, different calcium channels isoforms are targeted by clinically active drugs such as analgesics, general anesthetics, antiepileptics and cardioactive drugs, 12,15,[22][23][24] and mutations in various calcium channel isoforms have been associated with conditions such as familial migraine, deafness, epilepsy, cardiac arrhythmias and ataxia (reviewed in refs. 25 and 26).…”

Section: Introductionmentioning

confidence: 99%

Signaling complexes of voltage-gated calcium channels

2011

View full text Add to dashboard Cite

“…39 Protein SUMOylation has been reported to modulate neurotransmitter release 36 perhaps via N-type calcium channels that, in turn, are modulated by CRMP2. In summary, SUMO regulation of CRMP2/CaV2.2 signaling may have important implications for chronic pain because CaV2.2 channels are genetically 40,41 and clinically 28,42,43 validated targets for pain management. Future work will also investigate whether SUMOylation of CRMP2 affects its other functions, as well as how it regulates its other interactions.…”

Section: Discussionmentioning

confidence: 99%

“…We are focusing on protein-protein interactions that regulate CaV2.2-channels that are essential mediators of the neurotransmitter release pathway in nerve terminals, 25,26 including those involved in pain networks. 27,28 Our approach has been to identify modulators of CaV2.2 and then block these interactions to circumvent problems associated with drugs that directly block this channel. Here, we identify a putative SIM in CRMP2, removal of which has functional consequences on CRMP2's regulation of calcium influx via CaV2.2.…”

Section: Complex In Vivo Reduces Painmentioning

confidence: 99%