Neurological disorders

Panic disorder; Social phobia; Agoraphobia

Infusion of ectopic CCK4 peptide has been shown to induce panic-like symptoms in both panic disorder affected patients and non-affected controls, indicating that abnormal expression or activity of the CCK4 protein may play a role in the pathology of panic disorder and other anxiety disorders. These experimentally-induced panic symptoms can be prevented in a dose-dependent manner by the administration of selective CCK4 antagonists. In addition, a C-to-T transition mutation was observed at position -36 in the GC box of the CCK4 promoter sequence in patients with panic disorder. This suggests that the disorder may be due to aberrant expression of CCK4 rather than mutation of the protein sequence. Furthermore, ligands of the TSPO protein have been demonstrated to have potent anxiolytic activity in humans, thus they are thought to be useful for the treatment of anxiety-related disorders, including panic disorder. TSPO is an 18 KDa protein located in the outer mitochondrial membrane that mediates mitochondrial cholesterol import and neurosteroid biosynthesis. These endogenous metabolites have been shown to be significantly reduced during panic attacks and other anxiety-related events. Stimulants of this protein were shown to counteract the effects of CCK4-mediated panic attacks in an experimental context, indicating a link between CCK4 activity and neurosteroid levels in anxiety disorders. In animal studies, mice with mutated CCK4 protein display disrupted neural tube closure and abnormal stereociliary bundle orientation, indicating a role for the protein in neurodevelopment. Additionally, CCK4 protein is dynamically localized during the establishment of hair-cell polarity and appears to be a critical vertebrate regulator of planar cell polarity during development. Therefore, abnormal expression of CCK4 appears to be a contributing factor to the development of anxiety disorders (e.g. panic disorder), potentially through an interaction with neurosteroids or efffect on neurodevelopment. Panic disorder is a form of anxiety disorder characterized by panic attacks, which are sudden onset feelings of terror in non-dangerous situations. Social phobia is a phobic disorder characterized by a fear of specific public or social situations, interations with other people, or being evaluated/scrutinized. Agoraphobia is a phobic disorder characterized by the specific fear of being in a place/situation from which escape is difficult or embarrassing.
 

The COSMIC website notes an up-regulated expression score for CCK4 in diverse human cancers of 606, which is 1.3-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 20 for this protein kinase in human cancers was 0.3-fold of the average score of 60 for the human protein kinases.

Insertional mutagenesis studies in mice have not yet revealed a role for this protein kinase in mouse cancer oncogenesis.

Percent mutation rates per 100 amino acids length in human cancers: 0.06 % in 25658 diverse cancer specimens. This rate is only -18 % lower than the average rate of 0.075 % calculated for human protein kinases in general.

Highest percent mutation rates per 100 amino acids length in human cancers: 0.34 % in 854 skin cancers tested; 0.32 % in 1243 large intestine cancers tested; 0.17 % in 589 stomach cancers tested; 0.12 % in 1941 lung cancers tested.

None > 6 in 20,941 cancer specimens

Only 3 deletions, 4 insertions or 1 complex mutation are noted on the COSMIC website.