PLCB1 in heart failure Flashcards
What is PLCB1
PLC isoenzymes play an important role in activating intracellular signalling pathways. Upon activation, PIP2 is converted into IP3 and DAG which participate in a variety of intracellular processes including hypertrophy, calcium movement amongst others
Arthur et al 2001
They identified that cardiomyoctes express different isoforms, however PLCB was the one coupled to alpha 1 adrenergic receptors
Filtz et al 2009
They identified that PLCB has two splice variants in the heart including PLCB1a and PLCB1b. They both differ in their C-terminal domains, and while PLCB1a is usually cytoplasmic associated, the PLCB1b is membrane associated and it usually interacts with scaffolding proteins. They identified that PLCB1b was more associated with Gq activation
They isolated NRVMs and in 1/2 they infected with a sham green protein, while the other half were infected with PLCB1b. IP3 activation was measured as the amount of total IP3 accumulation.
In PLCB1b cells, there was increased IP3 activity, and there was also increased cell area as seen by the phalloidin stain. There was also elevated protein to DNA ratio and total ANP released in cells with PLCB1b compared to PLCB1a.
On the addition of a PLCB1b blocker, PLCB1-CT, there was a reduction in PLC activity, and a reduction in the hypertrophy and increased cell size. There was also a reduction in the NA and propranolol activity and hypertrophy, suggesting that the Gq-mediated PLC pathway was blocked
Dent et al 2004
In Sprague Dawley rats subjected to an AV shunt by the fine needle technique, to create a volume overloaded model of HF, they examined the time changes needed for the changes in expression of various PLC activated substances.
They measure changes at week 1,2,4,8,16.
By day 3, there was a 2x increase in PLCB1, and by the first week, a 7x increase in PLCB1. What happened however at week 4 was that the PLCB1 activity was not visible anymore, and LV hypertrophy started to occur. These findings could explain the reduction in inotropy in HF. As a result, they could be a potential drug target
By over-expression of PLCB1b peptide inhibitor lead to decreased hypertrophy response to alpha 1 adrenoreceptor stimulation
Woodcock et al 2015 and 2016
As PLCB1a and PLCB1b differ by their C-terminal which has a proline instead of PDZ domain. They identified a SHANK3 site as an important site of attachment for this C-terminal. As a result, the interaction between SHANK3 and C-terminal could be a potential drug target for reducing hypertrophy
Woodcock et al 2016
Based on this, they developed a PLCB1b-CT targeted at that SHANK3 site. This was delivered IV to mice with contractile dysfunction in vivo. Other mice were given IV blank viruses. Both of them then underwent TAC. The PLCB1b-CT mice had reduced contractile dysfunction and lung congestion in vivo suggesting a novel therapeutic
