title: Identification of CaV channel types expressed in muscle afferent neurons.
abstract: Cardiovascular adjustments to exercise are partially mediated by group III/IV (small to medium) muscle afferents comprising the exercise pressor reflex (EPR). However, this reflex can be inappropriately activated in disease states (e.g., peripheral vascular disease), leading to increased risk of myocardial infarction. Here we investigate the voltage-dependent calcium (CaV) channels expressed in small to medium muscle afferent neurons as a first step toward determining their potential role in controlling the EPR. Using specific blockers and 5 mM Ba(2+) as the charge carrier, we found the major calcium channel types to be CaV2.2 (N-type) > CaV2.1 (P/Q-type) > CaV1.2 (L-type). Surprisingly, the CaV2.3 channel (R-type) blocker SNX482 was without effect. However, R-type currents are more prominent when recorded in Ca(2+) (Liang and Elmslie 2001). We reexamined the channel types using 10 mM Ca(2+) as the charge carrier, but results were similar to those in Ba(2+). SNX482 was without effect even though ∼27% of the current was blocker insensitive. Using multiple methods, we demonstrate that CaV2.3 channels are functionally expressed in muscle afferent neurons. Finally, ATP is an important modulator of the EPR, and we examined the effect on CaV currents. ATP reduced CaV current primarily via G protein βγ-mediated inhibition of CaV2.2 channels. We conclude that small to medium muscle afferent neurons primarily express CaV2.2 > CaV2.1 ≥ CaV2.3 > CaV1.2 channels. As with chronic pain, CaV2.2 channel blockers may be useful in controlling inappropriate activation of the EPR.
authors.affiliation: The Baker Laboratory of Pharmacology, Department of Pharmacology, AT Still University of Health Sciences, Kirksville, Missouri;
authors.forename: Renuka
authors.initials: R
authors.lastname: Ramachandra
authors.forename: Bassil
authors.initials: B
authors.lastname: Hassan
authors.forename: Stephanie G
authors.initials: SG
authors.lastname: McGrew
authors.forename: James
authors.initials: J
authors.lastname: Dompor
authors.forename: Mohamed
authors.initials: M
authors.lastname: Farrag
authors.forename: Victor
authors.initials: V
authors.lastname: Ruiz-Velasco
authors.forename: Keith S
authors.initials: KS
authors.lastname: Elmslie
mesh_terms: D000200:Action Potentials; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D001464:Barium / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D005727:Ganglia, Spinal / Q000166:cytology / Q000502:physiology; D006801:Humans; D008297:Male; D018482:Muscle, Skeletal / Q000294:innervation* / Q000502:physiology; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012018:Reflex
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D001464:Barium; D000255:Adenosine Triphosphate
keywords: CaV2.1; CaV2.2; CaV2.3; dorsal root ganglia neurons; exercise pressor reflex