Intrinsic Adrenal TWIK-Related Acid-Sensitive TASK Channel Dysfunction Produces Spontaneous Calcium Oscillations...

Area of Science:

• Endocrinology
• Molecular Biology
• Ion Channel Physiology

Background:

• Mutations in calcium-regulating genes are linked to angiotensin II-independent aldosterone production.
• TWIK-related acid-sensitive potassium channels (TASK-1 and TASK-3) in zona glomerulosa (zG) cells are implicated in aldosterone autonomy.

Purpose of the Study:

• To investigate if TASK channel dysfunction in native zG cell rosette assemblies causes spontaneous calcium oscillations.
• To determine if TASK channel dysfunction is sufficient to drive substantial aldosterone autonomy independent of angiotensin II.

Main Methods:

• Calcium imaging in adrenal slices from a mouse model with zG-specific TASK channel deletion (zG-TASK-loss-of-function) using a zG-specific calcium reporter (GCaMP3).
• Pharmacological inhibition of TASK channels in wild-type (WT) adrenal slices.
• Measurement of acute aldosterone production from adrenal slice cultures.

Main Results:

• Adrenal-specific genetic deletion or pharmacological inhibition of TASK channels induced spontaneous oscillatory bursting calcium activity in zG cells.
• This spontaneous activity resulted in a 2.4-fold increase in aldosterone production, comparable to angiotensin II stimulation in WT slices.
• Spontaneous and inhibitor-evoked aldosterone production were unresponsive to angiotensin II over a wide concentration range.

Conclusions:

• Spontaneous activity in zG cells, driven by intrinsic changes in resting-state conductance (TASK channel dysfunction), can significantly contribute to angiotensin II-independent aldosterone production.
• This study provides proof of principle that intrinsic channel activity is sufficient to cause aldosterone autonomy in native adrenal tissue.