Upstream open reading frames regulate cannabinoid receptor 1 expression under baseline conditions and during cellular stress

• Two of the five CNR1 variants contain functionally relevant uORFs.
• CNR1 uORFs modulate protein expression both under baseline and stress conditions.
• To modulate protein expression CNR1 uORFs make use of different mechanisms.
• CNR1 variant 4 uORFs demonstrate opposite effects at stress conditions.
• uORFs might help CNR1 variants to escape global translation repression during stress.

The cannabinoid receptor subtype 1 gene CNR1 is not only associated with phenotypes such as cognitive performance, addiction and anxiety, but is also known to be crucially involved in responses to acute and chronic psychological and cellular stress conditions. Functional analysis of the 5' untranslated regions of the five known mRNA variants of the human CNR1 gene revealed that two of these variants contain upstream open reading frames that are able to modulate gene expression both under baseline condition and conditions of cellular stress including hypoxia, glucose restriction and hyperthermia. The upstream open reading frames might provide a mechanism that enables the cannabinoid 1 receptor to escape the general repression of protein synthesis that is typical for conditions of cellular stress.