Evolution of the N-Terminal Regulation of Cardiac Troponin I for Heart Function of Tetrapods: Lungfish Presents an Example of the Emergence of Novel Submolecular Structure to Lead the Capacity of Adaptation

Rasmussen, Monica; Feng, Han‐Zhong; Jin, Jian‐Ping

doi:10.1007/s00239-021-10039-9

Cited by 5 publications

(30 citation statements)

References 62 publications

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“…7). Our data showed that in lungfish, a PKA phosphorylated band co-localised with the confirmed TnI location (in agreement with another recent study (Rasmussen et al 2022)), whereas in sharks and ray-finned fish, there was no co-localisation of PKA substrates and TnI band, consistent with predictions from the protein sequences and previous findings that the TnI of ray-finned fish exhibits little phosphorylation Patrick et al 2010). The PKA-phosphorylated band in both shark species at ~26 kDa (fig.…”

Section: Phosphorylation Of Cardiac-expressed Tni By Pkasupporting

confidence: 93%

“…TnC is a calmodulin-like protein that is part of the helix-loop-helix group of Ca 2+ binding proteins (Strynadka & James 1989), whilst TnI and TnT, which are closely related to one another (Chong & Jin 2009;Rasmussen & Jin 2021;Wei & Jin 2016), indirectly affect Ca 2+ affinity of Tn through protein-protein interactions within the complex (Lombardi et al 2008;Evans & Levine 1980;Hwang et al 2014). This mode of contraction activation is evolutionarily ancient and can be traced back to the earliest bilaterian animals ~700 million years ago (Barnes et al 2016;Rasmussen et al 2022;Cao et al 2019;Yaguchi et al 2017) In vertebrates, each striated muscle type (i.e. cardiac muscle, slow and fast twitch skeletal muscle) express a specific complement of TnC, TnI, and TnT genes (TNNC, TNNI and TNNT, respectively).…”

Section: Introductionmentioning

confidence: 99%

“…Several fundamental questions remain open regarding the evolution of the troponin I and T genes in vertebrates. Both teleost fish and mammals have TNNI paralogs that encode for cardiac-expressed TnIs, however, it is not clear whether these subunits are encoded by orthologous genes (Genge et al 2016;Rasmussen et al 2022).…”

Section: Introductionmentioning

confidence: 99%

“…In some ray-finned fishes, including teleosts and gar, there are two TNNC1 genes due to a lineage-specific gene duplication (Genge et al 2016). The evolutionary histories of TnI and TnT have received great attention (Wei & Jin 2016; Rasmussen et al 2022; Sheng & Jin 2016; MacLean et al 1997; Palpant et al 2010; Gross & Lehman 2016; Chong & Jin 2009; Hastings 1997; Shaffer & Gillis 2010; Genge et al 2016; Barnes et al 2016) and it is generally believed that, like mammals, most vertebrates possess three genes encoding TnI; slow skeletal (ssTnI; TNNI1 ), fast skeletal (fsTnI; TNNI2 ) and cardiac (cTnI; TNNI3 ), and three genes for TnT; slow skeletal (ssTnT: TNNT1 ), fast skeletal (fsTnT; TNNT3 ) and cardiac (cTnT: TNNT2 ). Because we explore a range of previously uncharacterised TNNI and TNNT genes and proteins outside of the three defined in mammals, and because non-mammalian vertebrates are known to express a variety of TNNI s in a given muscle type (Alderman et al 2012), we herein eschew the protein names that derive from muscle specific expression and instead adopt protein names based on the corresponding numbered gene i.e.…”

Section: Introductionmentioning

confidence: 99%

“…Particular interest has been paid to the evolution of TNNI3 , which in adult mammals is solely expressed in the heart and is distinguished from other vertebrate TNNI paralogs by a ‘unique’ N-terminal extension peptide (Sheng & Jin 2016; Shaffer & Gillis 2010; Rasmussen et al 2022). This N-terminal extension is an important regulatory structure (Sheng & Jin 2016) containing two protein kinase A (PKA) target serine residues that, when phosphorylated via ß-adrenergic stimulation, decrease myofilament Ca 2+ sensitivity (Fentzke et al 1999; Layland et al 2005; Robertson et al 1982, 198; Solaro et al 1976, 197), thereby increasing the rate of relaxation during diastole (Kentish et al 2001; Zhang et al 1995).…”

Section: Introductionmentioning

confidence: 99%

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A revised perspective on the evolution of troponin I and troponin T in vertebrates

Joyce

Ripley

Gillis

et al. 2022

Preprint

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The troponin (Tn) complex, responsible for the Ca2+ activation of striated muscle, is composed of three interacting protein subunits: TnC, TnI, and TnT, encoded by TNNC, TNNI, and TNNT genes. TNNI and TNNT are sister gene families, and in mammals the three TNNI paralogs (TNNI1, TNNI2, TNNI3), which encode proteins with tissue-specific expression, are each in close genomic proximity with one of the three TNNT paralogs (TNNT2, TNNT3, TNNT1, respectively). It has been widely presumed that all vertebrates broadly possess genes of these same three classes, although earlier work has overlooked jawless fishes (cyclostomes) and cartilaginous fishes (chimaeras, rays and sharks), which are distantly related to other jawed vertebrates. With a new phylogenetic and synteny analysis of a diverse array of vertebrates including these taxonomic groups, we define five distinct TNNI classes (TNNI1-5), with TNNI4 and TNNI5 being only present in non-mammalian vertebrates and typically found in tandem, and four classes of TNNT (TNNT1-4). These genes are located in four genomic loci that were generated by the 2R whole-genome duplication events. TNNI3, encoding ‘cardiac TnI’ in mammals, was independently lost in cartilaginous and ray-finned fishes. Ray-finned fishes predominantly express TNNI1 in the heart. TNNI5 is highly expressed in shark hearts and contains an N-terminal extension similar to that of TNNI3 found in tetrapod hearts. Given that TNNI3 and TNNI5 are distantly related, this supports the hypothesis that the N-terminal extension may be an ancestral feature of vertebrate TNNI and not an innovation unique to TNNI3, as has been commonly believed.

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Section: Phosphorylation Of Cardiac-expressed Tni By Pkasupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

A revised perspective on the evolution of troponin I and troponin T in vertebrates

Joyce

Ripley

Gillis

et al. 2022

Preprint

View full text Add to dashboard Cite

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Recent studies of the molecular mechanism of lusitropy due to phosphorylation of cardiac troponin I by protein kinase A

Marston

2022

J Muscle Res Cell Motil

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Ca2+ acts on troponin and tropomyosin to switch the thin filament on and off, however in cardiac muscle a more graded form of regulation is essential to tailor cardiac output to the body’s needs. This is achieved by the action of adrenaline on β1 receptors of heart muscle cells leading to enhanced contractility, faster heart rate and faster relaxation (lusitropy) via activation of the cyclic AMP-dependent protein kinase, PKA. PKA phosphorylates serines 22 and 23 in the N-terminal peptide of cardiac troponin I. As a consequence the rate of Ca2+release from troponin is increased. This is the key determinant of lusitropy. The molecular mechanism of this process has remained unknown long after the mechanism of the troponin Ca2+ switch itself was defined. Investigation of this subtle process at the atomic level poses a challenge, since the change in Ca2+-sensitivity is only about twofold and key parts of the troponin modulation and regulation system are disordered and cannot be fully resolved by conventional structural approaches. We will review recent studies using molecular dynamics simulations together with functional, cryo-em and NMR techniques that have started to give us a precise picture of how phosphorylation of troponin I modulates the dynamics of troponin to produce the lusitropic effect.

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N-terminal truncated cardiac troponin I enhances Frank-Starling response by increasing myofilament sensitivity to resting tension

Feng

Huang

Jin

2023

Journal of General Physiology

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Cardiac troponin I (cTnI) of higher vertebrates has evolved with an N-terminal extension, of which deletion via restrictive proteolysis occurs as a compensatory adaptation in chronic heart failure to increase ventricular relaxation and stroke volume. Here, we demonstrate in a transgenic mouse model expressing solely N-terminal truncated cTnI (cTnI-ND) in the heart with deletion of the endogenous cTnI gene. Functional studies using ex vivo working hearts showed an extended Frank-Starling response to preload with reduced left ventricular end diastolic pressure. The enhanced Frank-Starling response effectively increases systolic ventricular pressure development and stroke volume. A novel finding is that cTnI-ND increases left ventricular relaxation velocity and stroke volume without increasing the end diastolic volume. Consistently, the optimal resting sarcomere length (SL) for maximum force development in cTnI-ND cardiac muscle was not different from wild-type (WT) control. Despite the removal of the protein kinase A (PKA) phosphorylation sites in cTnI, β-adrenergic stimulation remains effective on augmenting the enhanced Frank-Starling response of cTnI-ND hearts. Force–pCa relationship studies using skinned preparations found that while cTnI-ND cardiac muscle shows a resting SL–resting tension relationship similar to WT control, cTnI-ND significantly increases myofibril Ca2+ sensitivity to resting tension. The results demonstrate that restrictive N-terminal deletion of cTnI enhances Frank-Starling response by increasing myofilament sensitivity to resting tension rather than directly depending on SL. This novel function of cTnI regulation suggests a myofilament approach to utilizing Frank-Starling mechanism for the treatment of heart failure, especially diastolic failure where ventricular filling is limited.

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Evolution of the N-Terminal Regulation of Cardiac Troponin I for Heart Function of Tetrapods: Lungfish Presents an Example of the Emergence of Novel Submolecular Structure to Lead the Capacity of Adaptation

Cited by 5 publications

References 62 publications

A revised perspective on the evolution of troponin I and troponin T in vertebrates

A revised perspective on the evolution of troponin I and troponin T in vertebrates

Recent studies of the molecular mechanism of lusitropy due to phosphorylation of cardiac troponin I by protein kinase A

N-terminal truncated cardiac troponin I enhances Frank-Starling response by increasing myofilament sensitivity to resting tension

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