Table 2.

Diseases associated with NCS-1

Field of study	Disorder/Sensory System	Organism	NCS-1’s Role/Observation	References
Neuro-Psychiatry	Bipolar disorder & Schizophrenia	human, rat	>50% higher levels of NCS-1 in the PFC compared to normal controls Chronic treatment with typical or atypical antipsychotics does not change NCS-1 expression in five brain regions: prefrontal cortex, hippocampus, striatum, cortex and cerebellum	[61, 74–80]
			Modulation of gamma band oscillations in the PPN in a concentration-dependent manner
			Lithium reduces effects of over expressed NCS -1 on PPN neurons
	Autistic spectrum disorder (ASD)	human	Rare missense mutation was identified in one autistic patient during study	[64, 65]
	X linked mental retardation	drosophil a	Potential drug target at the NCS-1/Ric8a interface	[30, 54 ]
	Addiction	human	Genetic polymorphisms are associated with cocaine addiction in African-Americans but not European Americans	[68, 69]
			Variations of the NCS-1 gene influence the efficacy of nicotine replacement therapy
	ADHD	rat	Methylphenidate induces changes in expression levels in rat hippocampus, prefrontal cortex and cerebellum	[81]
	Depression/Motivation	mouse	Deficiency appeared to result in anxiety- and depressive-like behaviors as well as in decreased willingness to work for food	[82, 83]
	Insomnia	rat	Dysregulation may lead to increased activity in PPN neurons. Potential mediated target for modulation of hyperarousal	[84]
	Parkinson’s disease (PD)	human, mouse	Post-mortem PD brains show increased NCS-1 mRNA suggesting increased NCS-1/D2- autoreceptor signalling in PD	[70, 85]
			Potential target in modulating the neuron activity and vulnerability to degeneration in PD
	CNS trauma	rat	Potential intracellular target for therapeutic intervention following injury to the central nervous system; NCS-1-induced neurite sprouting	[37]
	Neuro-degeneration (ND)	in vitro	Misfolding at physiological Ca2+ levels suggests potential link between Ca2+ dysregulation, protein misfolding and ND	[86]
	Memory	mouse	Deficiency shows impaired spatial learning and memory function as well as reduced exploration	[18–20, 87]
			Overexpression selectively in the adult murine dentate gyrus promotes a specific form of exploratory behavior
			Regulation of genes that are related to intrinsically motivated exploration, something that could be considered akin to curiosity.
			Up regulation of expression in the hippocampus through swimming training promotes memory
Oncology	CIPN	mouse	Prevention target through lithium pretreatment	[24, 46, 88 - 95]
	Taxol-induced cardiac arrhythmia	rat, mouse	Increased expression in cardiomyocytes after treatment with Paclitaxel leads to an acceleration of Ca2+ oscillations	[58]
	Breast cancer	human	Outcome predictor	[72]
Cardiology	Cardiac hypertrophy and stress	mouse	Increased expression in early stages of cardiac hypertrophy and potential mediator of hormone-induced progression of hypertrophy in adult hearts. Mediator of stress tolerance in cardiomyocytes; Upregulation in hearts after ischemia-reperfusion	[59, 73]
Infectious Diseases	Sepsis	rat	Low expression in prefrontal cortex may be associated with the pathophysiology of cognitive impairment during sepsis	[71]
Gastro-enterology	Colitis	rat, ENS	Selective loss of NCS-1 expression after DNBS-induced colitis	[96]
Urology	Erectile dysfunction (ED)	rat, penile tissue	Potential target in the treatment of ED, up-regulation after administration of tadalafil	[97]
Developmenta l	Olfactory system	mouse	Expression in olfactory epithelium during development, down-regulation of axonal expression after synapse formation	[27]
Biology
	Eye	chick/rat	Neuronal process outgrowth and synaptogenesis in the retina	[98, 99]
	Inner ear	zebrafish	Signaling pathway for semicircular canal formation, Knockdown of NCS-1a mRNA blocked formation of semicircular canals.	[100, 101]
	Heart	mouse	High expression in the heart during fetal period and decline after birth; regulator of excitation-contraction coupling in fetal and neonatal hearts through enhancement of Ca(2+) signals	[59, 102, 103]

ADHD: attention deficit hyperactivity disorder, CIPN: Chemotherapy induced peripheral neuropathy, CNS: Central nervous system, DNBS: dinitrobenzene sulfonic acid, ENS: Enteric Nervous System, PPN: pedunculopontine nucleus