All modern biology is based on the principle that information is stored in genes and realized in proteins. It would be logical to assume that the number of genes in an organism should scale with the organism's complexity. Surprisingly, recent genome sequencing projects do not support this hypothesis. Drastically different organisms, such as humans, flies and worms, carry a more or less common set of genes. What then is the genetic basis for complexity? RNA editing, a process that changes and increases genetic information, could play an important role.
My lab focuses on a form of editing mediated by the hydrolytic deamination of adenosine residues in mRNAs. By changing adenosine to inosine, which is read by the ribosome as guanosine, codons can be mutated and protein structure and function changed. Although adenosine deamination occurs in the nervous system of all metazoans, its biological significance is poorly understood. In mammals, relatively few mRNA substrates for A→I editing have been identified, most encoding proteins involved in excitability. These editing events, however, are absolutely critical for survival.
Recent investigations have identified a surprisingly large number of edited substrates in Drosophila and Loligo, suggesting that editing in invertebrates is a particularly robust process. Editing permits multiple proteins from a single gene. Which mRNAs are targeted and how is protein function changed? My research examines RNA editing in squid and octopus and specifically focuses on voltage dependent K+ channels, the Na+/K+ ATPase and double-stranded RNA specific adenosine deaminase, an editing enzyme. Molecular biological and biochemical approaches are used to examine which codons are modified and how the editing process is regulated. Electrophysiological approaches are used to understand how changes made by editing affect channel and transporter function. These data are important because they provide insight on how A→I editing influences the evolution of nervous function.
- Selected Publications
1: Garrett S, Rosenthal JJ. RNA Editing Underlies Temperature Adaptation in K+
Channels from Polar Octopuses. Science. 2012 Jan 5. [Epub ahead of print] PubMed
2: Castillo JP, De Giorgis D, Basilio D, Gadsby DC, Rosenthal JJ, Latorre R,
Holmgren M, Bezanilla F. Energy landscape of the reactions governing the Na+
deeply occluded state of the Na+/K+-ATPase in the giant axon of the Humboldt
squid. Proc Natl Acad Sci U S A. 2011 Dec 20;108(51):20556-61. Epub 2011 Dec 5.
PubMed PMID: 22143771; PubMed Central PMCID: PMC3251152.
3: Keegan LP, McGurk L, Palavicini JP, Brindle J, Paro S, Li X, Rosenthal JJ,
O'Connell MA. Functional conservation in human and Drosophila of Metazoan ADAR2
involved in RNA editing: loss of ADAR1 in insects. Nucleic Acids Res. 2011 Sep
1;39(16):7249-62. Epub 2011 May 27. PubMed PMID: 21622951; PubMed Central PMCID:
4: Gonzalez C, Lopez-Rodriguez A, Srikumar D, Rosenthal JJ, Holmgren M. Editing
of human K(V)1.1 channel mRNAs disrupts binding of the N-terminus tip at the
intracellular cavity. Nat Commun. 2011 Aug 16;2:436. doi: 10.1038/ncomms1446.
PubMed PMID: 21847110; PubMed Central PMCID: PMC3265383.
5: Galarza-Muñoz G, Soto-Morales SI, Holmgren M, Rosenthal JJ. Physiological
adaptation of an Antarctic Na+/K+-ATPase to the cold. J Exp Biol. 2011 Jul
1;214(Pt 13):2164-74. PubMed PMID: 21653810; PubMed Central PMCID: PMC3110501.
6: Colina C, Palavicini JP, Srikumar D, Holmgren M, Rosenthal JJ. Regulation of
Na+/K+ ATPase transport velocity by RNA editing. PLoS Biol. 2010 Nov
23;8(11):e1000540. PubMed PMID: 21124885; PubMed Central PMCID: PMC2990702.
7: Palavicini JP, O'Connell MA, Rosenthal JJ. An extra double-stranded RNA
binding domain confers high activity to a squid RNA editing enzyme. RNA. 2009
Jun;15(6):1208-18. Epub 2009 Apr 23. PubMed PMID: 19390115; PubMed Central PMCID:
8: Rosenthal JJ, Seibel BA, Dymowska A, Bezanilla F. Trade-off between aerobic
capacity and locomotor capability in an Antarctic pteropod. Proc Natl Acad Sci U
S A. 2009 Apr 14;106(15):6192-6. Epub 2009 Mar 26. PubMed PMID: 19325127; PubMed
Central PMCID: PMC2669364.
9: Colina C, Rosenthal JJ, DeGiorgis JA, Srikumar D, Iruku N, Holmgren M.
Structural basis of Na(+)/K(+)-ATPase adaptation to marine environments. Nat
Struct Mol Biol. 2007 May;14(5):427-31. Epub 2007 Apr 29. PubMed PMID: 17460695.
10: Keegan LP, Rosenthal JJ, Roberson LM, O'Connell MA. Purification and assay of
ADAR activity. Methods Enzymol. 2007;424:301-17. PubMed PMID: 17662847.
11: Roberson LM, Rosenthal JJ. An accurate fluorescent assay for quantifying the
extent of RNA editing. RNA. 2006 Oct;12(10):1907-12. Epub 2006 Sep 6. PubMed
PMID: 16957279; PubMed Central PMCID: PMC1581973.
12: Soto I, Rosenthal JJ, Blagburn JM, Blanco RE. Fibroblast growth factor 2
applied to the optic nerve after axotomy up-regulates BDNF and TrkB in ganglion
cells by activating the ERK and PKA signaling pathways. J Neurochem. 2006
Jan;96(1):82-96. Epub 2005 Nov 3. PubMed PMID: 16269011.
13: Bhalla T, Rosenthal JJ, Holmgren M, Reenan R. Control of human potassium
channel inactivation by editing of a small mRNA hairpin. Nat Struct Mol Biol.
2004 Oct;11(10):950-6. Epub 2004 Sep 7. PubMed PMID: 15361858.
14: Rosenthal JJ, Gilly WF. Identified ion channels in the squid nervous system.
Neurosignals. 2003 May-Jun;12(3):126-41. Review. PubMed PMID: 12904686.
15: Rosenthal JJ, Bezanilla F. A comparison of propagated action potentials from
tropical and temperate squid axons: different durations and conduction velocities
correlate with ionic conductance levels. J Exp Biol. 2002 Jun;205(Pt 12):1819-30.
PubMed PMID: 12042340.
16: Rosenthal JJ, Bezanilla F. Extensive editing of mRNAs for the squid delayed
rectifier K+ channel regulates subunit tetramerization. Neuron. 2002 May
30;34(5):743-57. PubMed PMID: 12062021.
17: Liu TI, Lebaric ZN, Rosenthal JJ, Gilly WF. Natural substitutions at highly
conserved T1-domain residues perturb processing and functional expression of
squid Kv1 channels. J Neurophysiol. 2001 Jan;85(1):61-71. PubMed PMID: 11152706.
18: Rosenthal JJ, Bezanilla F. Seasonal variation in conduction velocity of
action potentials in squid giant axons. Biol Bull. 2000 Oct;199(2):135-43. PubMed
19: Rosenthal JJ, Liu TI, Gilly WF. A family of delayed rectifier Kv1 cDNAs
showing cell type-specific expression in the squid stellate ganglion/giant fiber
lobe complex. J Neurosci. 1997 Jul 1;17(13):5070-9. PubMed PMID: 9185544.
20: Mathes C, Rosenthal JJ, Armstrong GM, Gilly WF. Fast inactivation of delayed
rectifier K conductance in squid giant axon and its cell bodies. J Gen Physiol.
1997 Apr;109(4):435-48. PubMed PMID: 9101403; PubMed Central PMCID: PMC2219430.