Journal
JOURNAL OF NEUROCHEMISTRY
Volume 154, Issue 2, Pages 158-176Publisher
WILEY
DOI: 10.1111/jnc.14966
Keywords
adrenal chromaffin cell; nicotinic acetylcholine receptor; pituitary gland; alpha-conotoxin
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Funding
- National Institutes of Health [DA042749, GM103801, GM48677]
- FP7 Ideas: European Research Council
- Ministerio de Ciencia e Innovacion [BFU2012-30997, BFU2015-69092]
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Adrenal chromaffin cells release neurotransmitters in response to stress and may be involved in conditions such as post-traumatic stress and anxiety disorders. Neurotransmitter release is triggered, in part, by activation of nicotinic acetylcholine receptors (nAChRs). However, despite decades of use as a model system for studying exocytosis, the nAChR subtypes involved have not been pharmacologically identified. Quantitative real-time PCR of rat adrenal medulla revealed an abundance of mRNAs for alpha 3, alpha 7, beta 2, and beta 4 subunits. Whole-cell patch-clamp electrophysiology of chromaffin cells and subtype-selective ligands were used to probe for nAChRs derived from the mRNAs found in adrenal medulla. A novel conopeptide antagonist, PeIA-5469, was created that is highly selective for alpha 3 beta 2 over other nAChR subtypes heterologously expressed in Xenopus laevis oocytes. Experiments using PeIA-5469 and the alpha 3 beta 4-selective alpha-conotoxin TxID revealed that rat adrenal medulla contain two populations of chromaffin cells that express either alpha 3 beta 4 nAChRs alone or alpha 3 beta 4 together with the alpha 3 beta 2 beta 4 subtype. Conclusions were derived from observations that acetylcholine-gated currents in some cells were sensitive to inhibition by PeIA-5469 and TxID, while in other cells, currents were sensitive only to TxID. Expression of functional alpha 7 nAChRs was determined using three alpha 7-selective ligands: the agonist PNU282987, the positive allosteric modulator PNU120596, and the antagonist alpha-conotoxin [V11L,V16D]ArIB. The results of these studies identify for the first time the expression of alpha 3 beta 2 beta 4 nAChRs as well as functional alpha 7 nAChRs by rat adrenal chromaffin cells.
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