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Exciting peptide drugs for heart disease. RNA sensing of basic pH. Biased hormonal signaling. Read about papers on these topics recently published in the Journal of Biological Chemistry.

Exciting peptide drugs for heart disease

The venom molecule GsMTx4 was isolated from the Chilean flame tarantula
Grammostola spatulata, which is native to South America.

Atrial fibrillation, a heart disease characterized by faster and often irregular heartbeats, is associated with passive stretching of heart chamber muscle. While current treatments are expensive and have negative side effects, drugs that target the excitatory current-mediating stretch-activated channels, or SACs, in the heart could be extremely effective.

The venom from a species of tarantula can inhibit similar mechano-sensitive ion channels. In in the Journal of Biological Chemistry, a team of researchers from Xuzhou Medical University in China sought to identify features of the venom molecule GsMTx4, such as the inhibitor–cystine knot or specific loop folds, that could be used to enhance the specificity of peptide drugs against SACs. The authors designed two types of short peptides that were capable of specifically inhibiting a stretch-activated potassium channel also known as SAKcaC. One peptide consisted of a short loop region of GsMTx4, and the other mimicked the fold of this region.

The finding that both types of peptides could inhibit normal SAKcaC but not modified inactive SAKcaC indicated that these peptides act on the mechanical gating of the ion channel. This could form the basis of a new strategy for anti-arrhythmic drug development.

RNA sensing of basic pH

One strategy used by bacteria to regulate gene expression is a folded structure of the 5’-untranslated regions of messenger RNAs, also known as a riboswitch, which can obscure the ribosome binding site. One such riboswitch is the pH-responsive element, or PRE, which blocks translation of the mRNA at neutral pH but unfolds and refolds at alkaline (basic) pH, allowing the ribosome to translate the message into protein. Previous studies have suggested that alkaline pH–induced pausing of the RNA polymerase during transcription causes a kind of traffic jam and allows time for the PRE to refold into a translationally active form.

In published in the Journal of Biological Chemistry, Christine Stephen and Tatiana Mishanina at the University of California, San Diego, demonstrate that alkaline pH does affect RNA polymerase pausing but in the other direction — it actually decreases the length of the pause. These results suggest that the RNA itself may be involved in sensing high pH and may induce its own conformational change to allow co-transcriptional translation independent of RNA polymerase pausing. The authors propose that a pH-induced change in 3D RNA structure could lead to the observed effects and expand our knowledge of the repertoire of mechanisms of gene regulation.

Biased hormonal signaling

The parathyroid hormone-related protein, or PTHrP, is involved in many developmental processes, including breast, bone and tooth formation. PTHrP has been shown to initiate two simultaneous downstream G protein–coupled receptor signaling cascades triggered by secondary messengers cAMP and Ca2+. In addition, PTHrP is alternatively spliced in the body, but most of our knowledge of its various roles is based on studies performed with its 36–amino acid N-terminal fragment rather than the whole protein.

Karina Peña and others in Jean-Pierre Vilardaga’s laboratory at the University of Pittsburgh investigated the effects of downstream signaling using the whole 141–amino acid protein hormone. Using techniques such as FRET to record real-time cAMP production, the researchers confirmed that the N-terminal PTHrP fragment induces a transient cAMP response, while the complete PTHrP induces a sustained cAMP response. Furthermore, using an antagonist that blocks this sustained cAMP production, they showed this signaling was dependent on ligand–receptor complexes at the cell surface, rather than those being cycled via endocytosis. The team proposed that a positively charged sequence not present in the N-terminal PTHrP allows the hormone to attach to the cell surface.

Together, these findings suggest PTHrP signaling is biased toward cAMP production at the cell membrane rather than Ca2+-based downstream signaling.