Department of Physiology
Life Sciences | Medicine and Health Sciences | Neuroscience and Neurobiology
The G(q)-coupled tachykinin receptor (neurokinin-1 receptor [NK-1R]) modulates N-type Ca(2+) channel (Ca(V)2.2 or N channel) activity at two distinct sites by a pathway involving a lipid metabolite, most likely arachidonic acid (AA). In another study published in this issue (Heneghan et al. 2009. J. Gen Physiol. doi:10.1085/jgp.200910203), we found that the form of modulation observed depends on which Ca(V)beta is coexpressed with Ca(V)2.2. When palmitoylated Ca(V)beta2a is coexpressed, activation of NK-1Rs by substance P (SP) enhances N current. In contrast, when Ca(V)beta3 is coexpressed, SP inhibits N current. However, exogenously applied palmitic acid minimizes this inhibition. These findings suggested that the palmitoyl groups of Ca(V)beta2a may occupy an inhibitory site on Ca(V)2.2 or prevent AA from interacting with that site, thereby minimizing inhibition. If so, changing the orientation of Ca(V)beta2a relative to Ca(V)2.2 may displace the palmitoyl groups and prevent them from antagonizing AA's actions, thereby allowing inhibition even in the presence of Ca(V)beta2a. In this study, we tested this hypothesis by deleting one (Bdel1) or two (Bdel2) amino acids proximal to the alpha interacting domain (AID) of Ca(V)2.2's I-II linker. Ca(V)betas bind tightly to the AID, whereas the rigid region proximal to the AID is thought to couple Ca(V)beta's movements to Ca(V)2.2 gating. Although Bdel1/beta2a currents exhibited more variable enhancement by SP, Bdel2/beta2a current enhancement was lost at all voltages. Instead, inhibition was observed that matched the profile of N-current inhibition from Ca(V)2.2 coexpressed with Ca(V)beta3. Moreover, adding back exogenous palmitic acid minimized inhibition of Bdel2/beta2a currents, suggesting that when palmitoylated Ca(V)beta2a is sufficiently displaced, endogenously released AA can bind to the inhibitory site. These findings support our previous hypothesis that Ca(V)beta2a's palmitoyl groups directly interact with an inhibitory site on Ca(V)2.2 to block N-current inhibition by SP.
DOI of Published Version
J Gen Physiol. 2009 Nov;134(5):385-96. Link to article on publisher's site
The Journal of general physiology
Ganguli, Tora Mitra; Vitko, Iuliia; Perez-Reyes, Edward; and Rittenhouse, Ann R., "Orientation of palmitoylated CaVbeta2a relative to CaV2.2 is critical for slow pathway modulation of N-type Ca2+ current by tachykinin receptor activation" (2009). GSBS Student Publications. 1714.