Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023380 (lethargy)
 5,697 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several inherited human neurological disorders can be caused by mutations in genes encoding Ca2+ channel subunits. This review deals with known human and mouse calcium channelopathies of the central nervous system (CNS). The human diseases comprise: 1) a recessive retinal disorder, X-linked congenital stationary night blindness, associated with mutations in the CACNA1F gene, encoding alpha(1)1.4 subunits of L-type channels; and 2) a group of rare allelic autosomal dominant human neurological disorders including familial hemiplegic migraine, episodic ataxia type 2, and spinocerebellar ataxia type 6, all associated with mutations in the CACNA1A gene, encoding alpha(1)2.1 subunits of P/Q-type calcium channels. Mutations at the mouse orthologue of the CACNA1A gene cause a group of recessive neurological disorders, including the tottering, leaner, and rocker phenotypes with ataxia and absence epilepsy, and the rolling Nagoya phenotype with ataxia without seizures. Two other spontaneous mouse mutants with ataxia and absence epilepsy, lethargic and stargazer, have mutations in genes encoding a calcium channel auxiliary beta subunit and a putative calcium channel auxiliary gamma subunit. For each channelopathy, the review describes disease phenotype, channel genotype, and known functional consequences of the pathological mutations; in some cases, it also describes working hypothesis and/or speculations addressing the challenging question of how the alterations in channel function lead to selective cellular dysfunction and disease.
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PMID:Calcium channels and channelopathies of the central nervous system. 1189 Apr 56

Migraine is an episodic pain disorder whose pathophysiology is related to deficiency of serotonin signaling and abnormal function of the P/Q-type calcium channel, CACNA1A. Because the relationship of the CACNA1A channel to serotonin signaling is unknown and potentially of therapeutic interest we have used genetic analysis of the Caenorhabditis elegans ortholog of this calcium channel, UNC-2, to help identify candidate downstream effectors of the human channel. By genetic dissection of the lethargic mutant phenotype of unc-2, we have established an epistasis pathway showing that UNC-2 function antagonizes a transforming growth factor (TGF)-beta pathway influencing movement rate. This same UNC-2/TGF-beta pathway is required for accumulation of normal serotonin levels and stress-induced modulation of tryptophan hydroxylase (tph) expression in the serotonergic chemosensory ADF neurons, but not the NSM neurons. We also show that transgenic expression of the migraine-associated Ca2+ channel, CACNA1A, in unc-2 animals can functionally substitute for UNC-2 in stress-activated regulation of tph expression. The demonstration that these evolutionarily related channels share a conserved ability to modulate tph expression through their effects on TGF-beta signaling provides the first specific example of how CACNA1A function may influence levels of the critical migraine neurotransmitter serotonin.
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PMID:The voltage-gated calcium channel UNC-2 is involved in stress-mediated regulation of tryptophan hydroxylase. 1467 54

Migraine is a chronic episodic disorder that has been linked to abnormalities in serotonin signaling and abnormal function of a presynaptic voltage-gated calcium channel, CACNA1A. Although the importance of serotonin to migraine tendency suggests a link between serotonergic signaling and CACNA1A function, the nature of this connection remains unclear in vertebrate studies. This article reviews findings, based on an invertebrate model of CACNA1A dysfunction, which suggest a potential connection between serotonergic and calcium channel abnormalities in migraine. Neurons of the invertebrate species Caenorhabditis elegans express a voltage-gated calcium channel, UNC-2, which is the closest ortholog in C. elegans of human CACNA1A. Mutations in unc-2, the gene that encodes this invertebrate channel, cause the animals to be lethargic and uncoordinated. By identifying the genes that could be altered in such a way as to suppress the lethargic phenotype of unc-2, a signaling pathway has been identified through which UNC-2 calcium channel function antagonizes a transforming growth factor-beta (TGF-beta) pathway modulating locomotion. In C. elegans, serotonergic signaling can inhibit the rate of movement. The UNC-2/transforming growth factor-beta pathway identified regulates the expression of a gene encoding the rate-limiting enzyme for serotonin synthesis, tryptophan hydroxylase. The evolutionary and functional relationship between the UNC-2 channel and the migraine-associated CACNA1A channel was further confirmed through experiments showing that transgenic expression of human CACNA1A can suppress the lethargic and serotonin-deficient phenotypes of unc-2 mutant animals. The findings in this invertebrate model constitute the first direct demonstration of how CACNA1A function might affect the levels of serotonin, a neurotransmitter known to be important in migraine.
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PMID:Invertebrate modeling of a migraine channelopathy. 1692 61